
==== Front
Heliyon
Heliyon
Heliyon
2405-8440
Elsevier

S2405-8440(24)12357-2
10.1016/j.heliyon.2024.e36326
e36326
Research Article
Acute pulmonary embolism pretest probability estimation by d-dimer test, our modified, new ECG score and clinical prediction rules
Simon András a
Ámon Tamás a
Baracsi-Botos Viktória a
Pálfi Tímea a
Szőke Vince Bertalan a
Püspöki Zsuzsanna b
Varga Zoltán b
Kiss Loretta Zsuzsa c
Szénási Gábor d
Járai Zoltán ac
Vereckei András vereckei.andras@med.semmelweis-univ.hu
e⁎
a Department of Cardiology, South Buda Central Hospital, Saint Emeric University Teaching Hospital, Budapest, Hungary
b Hotel Service Department, South Buda Central Hospital, Saint Emeric University Teaching Hospital, Budapest, Hungary
c Heart and Vascular Center, Semmelweis University, Budapest, Hungary
d Institute of Translational Medicine, Semmelweis University, Budapest, Hungary
e Department of Medicine and Hematology, Semmelweis University, Budapest, Hungary
⁎ Corresponding author. Szentkirályi u. 46, Budapest, 1088, Hungary. vereckei.andras@med.semmelweis-univ.hu
14 8 2024
15 9 2024
14 8 2024
10 17 e363263 10 2023
8 8 2024
13 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Objectives

We investigated whether a sufficiently sensitive D-dimer test could exclude acute pulmonary embolism (acPE) as a stand-alone diagnostic test and compared our previously published, modified ECG score with the Wells and Geneva scores in the estimation of acPE pretest probability.

Methods

We retrospectively evaluated 345 patients who underwent chest CT angiography (CTA) for the suspicion of acPE. The pretest probability of acPE was assessed in 120 D-dimer negative [DD (−)] and 225 D-dimer positive [DD (+)] patients.

Results

Chest CTA verified acPE in 57/345 (16.5 %) patients and in 1/120 (0.8 %) DD (−) patient. In DD (−) patients the test accuracy (TA) and specificity (SP) of the ECG score (98 %, 99 %) were better than those of the Wells score (92.5 %, 92.4 %) (p = 0.063 and p < 0.05 respectively) and the Geneva score (76.7 %, 76.5 %) (p < 0.001 for both), the Wells score TA and SP were greater than those of the Geneva score (p < 0.001 for both). In DD (+) patients the SPs, TAs and positive predictive values (PPV) of the ECG score (94 %, 78.6 %, 69 %) and the Wells score (91.8 %, 75.1 %, 48 %) were greater than those of the Geneva score (71.3 %, 64.9 %, 38.2 %) (p < 0.001 for both SP and TA respectively, and p < 0.001 for PPV of the ECG score vs. the Geneva score and p < 0.05 for PPV of the Wells score vs. Geneva score), their sensitivities (SE) (36.4 %, 23.6 %) were less than that of the Geneva score (47.5 %) (p < 0.05 and p < 0.001 respectively). The ECG score's TA in a trend, its SE and PPV were significantly (p < 0.01 and p < 0.001) better than those of the Wells score.

Conclusion

In contrast to the current guidelines, a stand-alone high sensitivity DD (−) test, without prediction rules, could reliably exclude acPE. Our ECG score slightly outperformed the Wells score, the ECG score and Wells score far outperformed the Geneva score in the estimation of acPE pretest probability. An acPE diagnosis with the ECG score, in addition to the supportive diagnosis with the clinical prediction rules, may further increase the chance of true DD positivity.

Highlights

• Guidelines state that a negative D-dimer test can’t exclude acute pulmonary embolism (acPE) with high pretest probability.

• Our and other authors’ results proved that a high-sensitivity negative D-dimer test can exclude acPE, irrespective of its pretest probability.

• Our modified, new ECG score outperformed the Wells and Geneva scores in the estimation of acPE pretest probability.

• The Wells score outperformed the Geneva score in the estimation of acPE pretest probability.

Keywords

Pulmonary embolism
Electrocardiography
Clinical prediction rules
D-dimer test
==== Body
pmc1 Introduction

In contrast to the current guidelines [1,2], our clinical experience suggests that acute pulmonary embolism (acPE) can be safely ruled out by using a stand-alone negative high sensitivity (95–97 %) D-dimer test irrespective of the pretest probability of acPE determined by clinical prediction rules, such as the best known Wells and Geneva scores. In their original publication [3] Wells PS et al. showed that a negative D-dimer test can safely rule out acPE only when the Wells score was ≤4.0, indicating acPE unlikely, but a negative D-dimer test is less or not useful to rule out acPE when the Wells score was >4.0, indicating acPE likely. However they achieved these results by using a significantly less sensitive (82 %) whole blood agglutination assay (SimpliREDTH) D-dimer test. Therefore, due to the use of a less sensitive D-dimer test, they had more false negative D-dimer tests among patients with an acPE likely pretest probability determined by the Wells score [3]. However, other studies [[4], [5], [6]] using high-sensitivity enzyme-linked immunosorbent assay (ELISA) D-dimer tests showed very low percentage (<2 %) of false negative D-dimer tests, which is the expected false negative rate of a good diagnostic test (such as pulmonary angiography or chest CT angiography) recommended to rule out acPE. Perrier et al. [4] studied 918 consecutive patients presenting at the emergency ward with clinically suspected venous thromboembolism. A normal D-dimer concentration (<500 μg/L) by rapid ELISA test was found in 286 (31 %) patients. False negative D-dimer test was present in only 2/286 (0.7 %) patients due to the presence of deep venous thrombosis on ultrasonography, yielding a negative predictive value of 99.3 %. Kruip MJHA et al. [5] examined 234 patients with suspected acPE, a negative rapid ELISA D-dimer test was present in 100 (42 %) patients and only 1 (1 %) patient with a false negative D-dimer test was found due to acPE verified in segmental arteries by pulmonary angiography. Righini M et al. [6] investigated 1409 patients with suspected acPE. The high-sensitivity rapid quantitative ELISA D-dimer test was negative (<500 μg/L) in 439 (31 %) patients, and there was no false negative D-dimer test (0 %) in their study, irrespective of the acPE pretest probability determined by implicit clinical evaluation or the Geneva score. Fronas SG et al. [7] in a similar study, although investigating patients with suspected deep venous thrombosis and not with acPE, included 913 patients and 298 (33 %) had a negative high sensitivity D-dimer test result. Only 1 (0.3 %) had a false negative D-dimer test. This study confirmed the safety of a stand-alone negative D-dimer test for the exclusion of deep venous thrombosis irrespective of pretest probability of deep venous thrombosis determined by the three-category and two-category Wells scores. These studies [[4], [5], [6], [7]] supported our experience that a high-sensitivity D-dimer test may be used as a stand-alone test to rule out acPE irrespective of the pretest probability of acPE determined by clinical prediction rules. For this reason we conducted a retrospective study in consecutive patients, who underwent chest CT angiography examination for suspected acPE in order to investigate the ability of a stand-alone D-dimer test to rule out acPE. We also investigated the diagnostic performance of our previously published [8], new, modified ECG score and the Wells and Geneva scores in the determination of pretest probability of acPE.

2 Methods

2.1 Patients

After exclusion of patients with ongoing anticoagulant treatment for any indication, we studied retrospectively 1270 consecutive patients who underwent chest CT angiography (CTA)(with a 256 Slice GE Revolution CT Scanner) for suspected acPE between March 2020 and July 2021 in the South Buda Central Hospital, Saint Emeric University Teaching Hospital.

Of the 1270 cases, 925 patients had a D-dimer test available. The possible explanation why 345 patients underwent chest CTA without a D-dimer test was, that the doctor at the Emergency Department, who decided whether a chest CTA should be done, considered that many or most of these patients had a high probability of acPE. Another possible explanation may be that in this study we investigated patients who underwent chest CTA during the initial phase of COVID-19 pandemia and COVID-19 infection is associated with a predisposition to venous thromboembolism, for this reason many patients had associated pneumonia and acPE. Therefore, chest CTA was done without a D-dimer test in some patients who presented with a suspicion of COVID-19 infection and/or pneumonia as well. Among patients with a D-dimer test available 120 (13 %) patients had a negative high-sensitivity D-dimer test [<500 ng/mL in <50-year-old patients or age-adjusted D-dimer cutoff <(ageX10 ng//mL in patients aged ≥50 years) [9,10] and 805 (87 %) had a positive D-dimer test. Data of the 120 D-dimer negative [DD (−)] and the first consecutive 225 D-dimer positive [DD (+)] patients were used for analysis (Fig. 1). We analyzed the pretest probability of acPE and the ability of the negative D-dimer test to rule out acPE as a stand-alone diagnostic test. The study was approved by the Regional and Institutional Ethical Committee of the South Buda Central Hospital, Saint Emeric University Teaching Hospital (Reference number 3/2021). The requirement of written informed consent was waived due to the retrospective nature of the analyses.Fig. 1 Flow chart representing the study protocol.

Fig. 1

2.2 Laboratory tests

DD tests were performed by latex-enhanced immunoturbidimetric assay (D-dimer FS test, DiaSys Diagnostic Systems GmbH, Holzheim Germany), which has a diagnostic sensitivity [93 % (89–95)] comparable to that of the ELISA DD test [94 % (86–97)] [11].

2.3 Estimation of the pretest probability of acute pulmonary embolism

To determine the pretest probability of acPE we used our previously published [8] novel ECG score, based on the most important components of acPE pathomechanism with some modifications, and clinical prediction rules: the original versions of the Wells score and the Revised Geneva score. Fig. 2, Fig. 3 show our modified, novel ECG score in patients without or with right bundle branch block (RBBB) pattern. We had to omit the 5th criterion of the original version due to the retrospective nature of this study, as it requires the application of right-sided chest leads, which are not used in most cases during routine clinical work-up. In order to compensate for the omission of the 5th criterion, which may result in the decrease of the diagnostic accuracy of the novel ECG score, we added two additional criteria to the 3rd step of the novel ECG score applicable on the routine 12-lead ECG: 1) the presence of low voltage in the frontal leads defined as low QRS voltage (<0.5 mV) in the limb leads and 2) the presence of clockwise rotation in the precordial leads defined as an R/S ratio <1 in lead V5. These two ECG alterations are mainly due to right ventricular dilation, when the right ventricle extends farther to the left in the horizontal plane and pushes the left ventricle posteriorly, and to systemic fluid engorged tissues associated with acPE [12,13]. If T wave inversions were present in the inferior leads or in leads V1-3 together with an S wave in lead I, or inferior T wave inversions were present together with an inferior Q wave, we took them into account in the 1st step of the ECG score and we did not take them into account again in the 2nd step of the ECG score. Thus, the maximum value of the ECG score was 10 or 9 in patients without and with RBBB pattern respectively. If the ECG score value was ≥6/10 or ≥5/9, acPE diagnosis was established in patients without and with RBBB pattern respectively. The ECG score could not be applied in patients with left bundle branch block pattern, which was present in 4 DD (−) and 9 DD (+) patients, and in patients with pacemaker rhythm due to right ventricular pacing, which was present in 1 DD (−) and 3 DD (+) patients. Two investigators (AV and AS) blinded to the final clinical diagnosis analyzed all ECGs, by applying the modified, novel ECG score. The two investigators disagreed in the diagnosis of 25 (8 %) ECGs, but after re-evaluation of these cases they could resolve the disagreement by consensus. Data based on the consensus of the two investigators are presented.Fig. 2 Novel, modified ECG score sheet for patients without right bundle branch block (RBBB) pattern.

Fig. 2

Fig. 3 Novel, modified ECG score sheet for patients with right bundle branch block (RBBB) pattern.

Fig. 3

PE likely diagnosis was set up when the value of the Original version of the Wells score was ≥5, and when that of the Original version of the Revised Geneva score was ≥6, and PE unlikely diagnosis was established when these values were <5 and < 6 respectively. Low, intermediate and high pretest probability of acPE was diagnosed when the values of the Wells score were <2, 2–6, ≥7 and those of the Geneva score were <4, 4–10, ≥11 respectively. The pretest probability of acPE was determined in 345 patients (120 D-dimer negative and 225 D-dimer positive patients). Out of these 345 patients acPE was verified in 57 (16.5 %) patients by chest CTA. ECGs available or suitable for analysis were present in 306 patients (in 100 D-dimer negative and 206 D-dimer positive patients) (Fig. 1). DD (−) patients were followed for 3 months for the occurrence of venous thromboembolism.

2.4 Statistical analysis

Sensitivity, specificity and predictive values were calculated by GraphPadPrism version 6 for Windows (GraphPad Software Inc., La Jolla, CA, USA) and compared using a modified χ2 test without adjustment for multiple comparisons. Patient characteristics were compared with Fisher's exact test using also the GraphPadPrism version 6 for Windows. A p < 0.05 value was considered statistically significant. Significantly different likelihood ratios were indicated by disjoint (non-overlapping) 95 % confidence intervals. The kappa statistic was performed to quantify overall interobserver agreement using the IBM SPSS Statistics 25 for Windows software package (IBM Corp. Armonk, NY, USA). Overall interobserver agreement was defined as near complete if κ > 0.8, good if κ = 0.61 to 0.8, moderate if κ = 0.41 to 0.6, fair if κ = 0.21 to 0.4 and poor if κ < 0.2 [14].

3 Results

After the initial evaluation, the interobserver agreement was good (κ = 0.748) using the modified, novel ECG score.

3.1 Clinical and demographic patient characteristics

The mean age of the 345 patients in whom we estimated the acPE pretest probability was 58.5 ± 18.1 years, 186 (53.9 %) were male and all were Caucasian. There were no significant differences in any characteristics between the DD (−) and DD (+) patient groups, with the only exception of unavailable ECGs for analysis, which were more in the DD (−) group. The reasons why ECG analysis was not feasible in some patients were: unavailable ECG, poor quality ECG strip, LBBB pattern, pacemaker rhythm due to right ventricular pacing (Table 1). Patients incoming with complaints to the South Buda Central Hospital, Saint Emeric University Teaching Hospital are first investigated at the Emergency Department, where they decide whether the patient should be hospitalized or not, and if yes, to which department. Therefore, all evaluated patients were outpatients at the time of chest CTA examination. After this initial triage 60/120 (50 %) of DD (−) patients and 156/225 (69 %) DD (+) patients were subsequently hospitalized, although a greater percentage of DD (+) patients were hospitalized, the difference between the hospitalized patients in the DD (−) and DD (+) groups did not reach significance (not shown in Table 1).Table 1 Some demographic and clinical patient characteristics.

Table 1	All patients	DD (−) patients	DD (+) patients	
n = 345	n = 120	n = 225	
Age, mean (SD), years	58.5 (18.1)	58.3 (17)	58.7 (18.7)	
Sex, male, n(%)	186 (53.9)	63 (52.5)	123 (54.7)	
Chronic heart failure, n(%)	42 (12.2)	16 (13.3)	26 (11.6)	
Chronic lung disease, n(%)	56 (16.2)	22 (18.3)	34 (15.1)	
Active malignancy, n(%)	18 (5.2)	7 (5.8)	11 (4.9)	
Immobilization ≥3 days or surgery in the previous 4 weeks, n(%)	14 (4.1)	2 (1,7)	12 (5.3)	
ECG characteristics	n = 306	n = 100	n = 206	
 Intraventricular conduction disturbances	
 RBBB, n(%)	30 (9.8)	10 (10)	20 (8.9)	
 RBBB + LAFB, n(%)	8 (2.6)	4 (4)	4 (1.9)	
 LBBB, n(%)	13 (4.2)	4 (4)	9 (4.3)	
 NICD + LAFB, n(%)	1 (0.3)	0 (0)	1 (0.4)	
 Reasons why ECG analysis was not feasible	
 ECG was unavailable	21 (6.9)	15 (15)	6 (2.9)***	
 Poor quality ECG strip	1 (0.3)	0 (0)	1 (0.4)	
 LBBB, n(%)	13 (4.2)	4 (4)	9 (4.3)	
 Pacemaker rhythm, n(%)	4 (1.3)	1 (1)	3 (1.4)	
DD(−) = D-dimer test negative, DD(+) = D-dimer test positive, LAFB = left anterior fascicular block, LBBB = left bundle branch block, NICD = nonspecific intraventricular conduction disturbance, RBBB = right bundle branch block, SD = standard deviation. For various reasons ECG analysis was feasible in only 100 DD(−) and 206 DD(+) patients. We compared the DD(−) and DD(+) patient groups with statistical analysis. ***p < 0.001 vs. the DD(−) group.

3.2 Patients with a negative D-dimer test

In the DD (−) patients chest CTA revealed acPE in 1/120 (0.8 %). The test accuracy (TA) of the ECG score was 98 % and borderline (p = 0.063) better than that of the Wells score (92.5 %) and significantly (p < 0.001) better than that of the Geneva score (76.7 %). The TA of the Wells score was significantly (p < 0.001) better than that of the Geneva score (Table 2). The PE unlikely diagnosis established by the Wells and Geneva scores was considered an acPE negative, and PE likely diagnosis was considered an acPE positive diagnosis. Among the sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and positive and negative likelihood ratios [(+)LR, (−)LR] only the SP and NPV of the different methods used to estimate the pretest probability of acPE were comparable by statistical analysis. The reason for this was that the SE, PPV and (+)LR of the ECG score were 0 due to the 0 true positive acPE diagnosis established by the ECG score, and the (−)LRs of the Wells and Geneva scores were 0 due to their 0 false negative acPE diagnosis and consequently their SEs and NPVs were 100 %. The SP of the ECG score (99 %) was significantly (p < 0.05, p < 0.001) greater than that of the Wells score (92.4 %) and that of the Geneva score (76.5 %). The SP of the Wells score was also significantly (p < 0.001) greater than that of the Geneva score (Table 2). There was no difference in the NPV values of the ECG score, Wells and Geneva scores (98.7 %, 100 %, 100 % respectively). The (+) LR value (13.222 vs. 4.25) of the Wells score was significantly greater than that of the Geneva score indicated by the disjoint 95 % confidence intervals.Table 2 The sensitivity, specificity, test accuracy, predictive values and likelihood ratios of the tested methods in the DD (−) patients.

Table 2Methods	Sensitivity	Specificity	PPV	NPV	TA	(−)LR	(+)LR	
	%	%	%	%	%			
(n)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	
new, mod. ECG score	0 %	99 %###	0 %	99 %	98 %###	1.01	0	
(n=100)	(NA)	(97–101)	(NA)	(97–101)	(95.3–100.7)	(0.99–1.031)	(NA)	
Wells score orig.	100 %	92.4 %*, ###	10 %#	100 %	92.5 %###	0	13.222	
(n=120)	(100-100)	(87.7–97.2)	(0–28.6)	(100-100)	(87.8–97.2)	(NA)	(7.055–24.78)	
Geneva score rev.	100 %	76.5 %***	3.4 %	100 %	76.7***	0	4.25	
(n=120)	(100-100)	(68.8–84.1)	(0–10.1)	(100-100)	(69.1–84.2)	(NA)	(3.074–5.876)	
Statistical comparison could be performed only between the specificity and test accuracy of the novel ECG score, Wells and Geneva scores. This is because due to the 0 true positive acPE diagnosis established by the novel ECG score, the sensitivity, PPV and (+)LR of the novel ECG score were 0, and due to the 0 false negative acPE diagnosis set up by the Wells and Geneva scores, their sensitivities and NPVs were 100 %, and (−)LRs were 0. (AcPE was revealed by chest CTA only in 1/120(0.8 %) DD(−) patients). Significant between-groups difference in the likelihood ratios is indicated by disjoint (non-overlapping) 95 % confidence intervals. *p < 0.05, **p < 0.01, ***p < 0.001 vs. novel ECG score, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Geneva score. There was a borderline significant (p = 0.063) difference between the TA of the novel ECG score and the Wells score and the (+)LR of the Wells score was significantly better than that of the Geneva score indicated by the disjoint 95 % confidence intervals. 95%CI = 95 % confidence intervals, (−)LR = negative likelihood ratio, (+)LR = positive likelihood ratio, mod. = modified, NA = not applicable, NPV = negative predictive value, orig. = original, PPV = positive predictive value, rev. = revised, TA = test accuracy.

None of the DD (−) patients had venous thromboembolism during the 3 months follow-up period.

3.3 Patients with a positive D-dimer test

The TA of the ECG score (78.6 %) was the highest among DD (+) patients, it was only in a trend higher than that of the Wells score (75.1 %) and significantly (p < 0.01) higher than that of the Geneva score (64.9 %). The TA of the Wells score was significantly (p < 0.05) higher than that of the Geneva score (Table 3) The SE and PPV of the ECG score (36.4 % and 69 %) were significantly (p < 0.01 and p < 0.001 respectively) greater than those of the Wells score (23.6 % and 48.1 %) and its SP, PPV and (+)LR were significantly (p < 0.001 for the SP, p < 0.05 for the PPV) greater than that of the Geneva score [SP: 94 % vs. 71.3 %, PPV: 69 % vs. 38.2 %, (+)LR 6.101 vs. 1.659], but its SE was lower (p < 0.05) than that of the Geneva score (36.4 % vs. 47.5 %). There was no difference in the NPV and the (−)LR between the 3 methods. The SP and PPV of the Wells score (91.8 % and 48.1 %) were significantly (p < 0.001 for both) greater than those of the Geneva score (71.3 % and 38.2 %) and its SE (23.6 %) was significantly (p < 0.001) lower than that of the Geneva score (47.5 %) (Table 3).Table 3 The sensitivity, specificity, test accuracy, predictive values and likelihood ratios of the tested methods in the DD (+) patients.

Table 3Methods	Sensitivity	Specificity	PPV	NPV	A	(−)LR	(+)LR	
	%	%	%	%	%			
(n)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	(95 % CI)	
new, mod. ECG score	36.4 %#	94 %###	69 %###	80.2 %	78.6 %##	0.677	6.101	
(n=206)	(23.7–49.1)	(90.3–97.8)	(52.1–85.8)	(74.4–86.1)	(73–84.2)	(0.552–0.83)	(2.959–12.58)	
Wells score orig.	23.6 %**, ###	91.8 %###	48.1 %***, #	78.8 %	75.1 %#	0.832	2.87	
(n=225)	(12.4–34.9)	(87.6–95.9)	(29.3–67)	(73.1–84.5)	(69.5–80.8)	(0.714–0.97)	(1.438–5.728)	
Geneva score rev.	47.5 %*	71.3 %***	38.2 %***	78.5 %	64.9**	0.735	1.659	
(n=225)	(35–60.1)	(64.4–78.3)	(27.2–49.1)	(71.9–85.1)	(58.7–71.1)	(0.568–0.952)	(1.16–2.372)	
Significant between-groups difference in the likelihood ratios is indicated by disjoint (non-overlapping) 95 % confidence intervals. *p < 0.05, **p < 0.01, ***p < 0.001 vs. novel ECG score, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Geneva score. The (+)LR of the novel ECG score was significantly better than that of the Geneva score indicated by the disjoint 95 % confidence intervals 95%CI = 95 % confidence interval, (−)LR = negative likelihood ratio, (+)LR = positive likelihood ratio, mod. = modified, NPV = negative predictive value, orig. = original, PPV = positive predictive value, rev. = revised, TA = test accuracy.

3.4 Pretest probability of acPE in the DD (−) and DD (+) groups

In the DD (−) group acPE was diagnosed in 1/120 (0.8 %) patients and in 1/100 (1 %) patients, in whom the ECG was available or suitable for analysis, and the ECG score established an acPE diagnosis in 2/100 (2 %) patients, thus the acPE probability determined by the ECG score was 2 %. The 2-category (acPE unlikely or acPE likely diagnosis) Wells and Geneva scores revealed an acPE likely diagnosis in 9/120 (7.5 %) and 28/120 (23 %) patients respectively and an acPE likely diagnosis by both clinical prediction rules was established in 7/120 (5.8 %) patients. Both with the 3-category (low, intermediate, high pretest probability of acPE) Wells and Geneva scores a high probability acPE diagnosis was set up in 7/120 (5.8 %) patients.

In the DD (+) group 206 out of the 225 patients had ECGs available or suitable for analysis and 55/206 (27 %) of these patients were diagnosed with acPE by the chest CTA. The ECG score established an acPE diagnosis in 29/206 (14 %) patients. In the whole DD (+) group 56/225 (24.9 %) patients were diagnosed with acPE by chest CTA. The Wells score set up an acPE likely diagnosis in 27/225 (12 %) and high probability acPE diagnosis in 15/225 (6.7 %) patients and the Geneva score established an acPE likely diagnosis in 76/225 (34 %) and high probability acPE diagnosis in 8/225 (3.5 %) patients.

Thus. the probability of acPE established by the ECG score was closer to the real occurrence of acPE in the DD (−) group than the probability estimated with the clinical prediction rules, and similarly close in the DD (+) group.

4 Discussion

4.1 Major observations

In accordance with other previously published studies [[4], [5], [6],15,16], our study confirmed that among patients with a negative high-sensitivity D-dimer test result, false negative diagnosis of acPE occurred in ≤1 %. This is equal to or below the <1–2% rate of false negative results required from a reliable stand-alone diagnostic test, such as pulmonary angiography or chest CTA, to safely rule out acPE [[17], [18], [19]]. For example, after having a normal result chest CTA performed because of suspected acPE 1.2 % of patients were diagnosed with venous thrombosis [20,21] demonstrating that the suitability to exclude the diagnosis of acPE of a negative high-sensitivity D-dimer test matches that of chest CTA, which is used most commonly as a definitive test to confirm or rule out acPE. This, in contrast to the current recommendations in acPE guidelines [1,2], confirmed that a stand-alone negative high-sensitivity D-dimer test can safely rule out acPE irrespective of the estimation of pretest probability of acPE by clinical prediction rules. The safety of a stand-alone negative high-sensitivity D-dimer test to rule out acPE was further verified by our observation that none of the DD (−) patients left without anticoagulant treatment had a venous thromboembolism during the 3 months follow-up period. In the 1 false negative DD (−) case the chest CTA immediately revealed the acPE diagnosis, therefore this patient received anticoagulant treatment. The acceptable false negative rates of a diagnostic test used to rule out acPE depends on the PE prevalence in the investigated population [17]. Such acceptable adjusted thresholds of false negative rates have been proposed for different health care settings: 0.71–1.86 % for self-referral emergency care with an acPE prevalence of 7.5 %, 0.72–1.87 % in primary healthcare with an acPE prevalence of 8.9 %, 0.78–1.92 % in referred secondary care with an acPE prevalence of 20.2 %, and 0.8–1,95 % in hospitalized or nursing home care with an acPE prevalence of 24 %. In our investigated population the acPE prevalence was 16.5 %. Thus, in all health care settings the acceptable prevalence-adjusted threshold of false negative rate was <2 % and in our study the stand-alone negative high-sensitivity D-dimer test fulfilled this requirement [17]. Thus, the most important novelty of our study compared with other studies [[4], [5], [6]] investigating acPE patients and finding similar results by confirming the high NPV of a negative high-sensitivity D-dimer test, that in contrast to the authors of these other studies, we drew the in our opinion appropriate conclusion from these results. This conclusion is, which contradicts to the current acPE guidelines, that a stand-alone negative high-sensitivity D-dimer test can reliably rule out acPE in all cases, irrespective of the pretest probability of acPE determined by the clinical prediction rules.

4.2 Assessment of pretest acPE probability by our modified, novel ECG score and the Wells and Geneva scores

The diagnostic performance of our modified, novel ECG score was either significantly [the SP in DD (−) patients, the SE, PPV in DD (+) patients] or in a trend better than that of the Wells score both in the DD (−) and DD (+) patients, and with the exception of SE in DD (+) patients, it was significantly better in almost all diagnostic performance parameters than that of the Geneva score. The Wells score had a significantly better diagnostic performance than the Geneva score in almost all diagnostic performance parameters with the exception of SE, that was greater for the Geneva score in DD (+) patients. These results confirmed our previously published results [8] with the original, novel ECG score tested in our prospective study, which also showed a superior overall diagnostic accuracy of the novel ECG score in the prediction of pretest acPE probability compared with the Wells score and Geneva score and another ECG score (Daniel-ECG-score).

Since according to our results the negative high-sensitivity D-dimer test can safely rule out acPE as a stand-alone diagnostic test, the very high NPV of the ECG score, and Wells and Geneva scores in DD (−) patients does not increase the safety of ruling out acPE. However, due to its better diagnostic accuracy, the acPE diagnosis predicted by the ECG score may further increase the likelihood of acPE compared with the PE likely diagnosis established by the clinical prediction rules in DD (+) patients.

The decision that we will not evaluate all 805 DD (+) patients, but only the first consecutive 225 DD (+) patients, with the ECG score and clinical prediction rules was based on our expectation that we will obtain very similar results in this study to those published in our previous study [8] by using the original, new ECG score. The choice of the number of 225 consecutive patients was arbitrary, we estimated that this patient number will be sufficient to make an initial evaluation of the results, and see whether our expectation is met or not. Since after evaluating the first consecutive 225 DD (+) patients, our expectation to obtain very similar results to those published previously [8] was met, we considered superfluous to evaluate an additional 580 patients, just to further confirm these results. In order to justifiy this arbitrary decision, we performed a post-hoc analysis using The Post-hoc Power Calculator of the online ClinCalc software (https://clincalc.com/stats/Power.aspx) for the post hoc estimation of the dichotomous endpoints of our study in the 225 DD (+) patients. The estimation revealed that the study has 99.4 % and 82.9 % power for positive predictive value and sensitivity if calculated for the new, modified ECG score and the Wells score. As the general approach requires 80 % power, our study was sufficiently powered to reliably demonstrate whether our new, modified ECG score was superior to the two clinical prediction rules.

4.3 Limitations

The retrospective and single center nature of our study is a limitation. In the future prospective, multicentric studies should be conducted in a patient population with a high prevalence of acPE, and/or in different patient populations, such as those with cancer-associated venous thromboembolism, to verify the conclusions of our study. In a prospective study the right-sided ECG chest leads can also be applied, which increase the diagnostic accuracy of our novel ECG score, rendering possible the use of the 5th criterion of our original, novel ECG score.

5 Conclusions

Our results show that a stand-alone high sensitivity D-dimer test can safely rule out acPE, irrespective of the pretest probability of acPE, with a false negative rate as good as that required from a definitive diagnostic test, such as pulmonary angiography or chest CTA, to rule out or confirm the diagnosis of acPE. The overall diagnostic performance of our modified, novel ECG score was better in the estimation of acPE pretest probability than that of the Wells and Geneva scores, and the diagnostic performance of the Wells score was superior to that of the Geneva score. Therefore the acPE diagnosis established by the modified, novel ECG score due to its superior TA, in addition to the PE likely diagnosis by a clinical prediction rule, such as the Wells score, in patients with a positive D-dimer test, which in itself has a low PPV, may further increase the likelihood of acPE.

Ethics statement

The study was approved by the Regional and Institutional Ethical Committee of the South Buda Central Hospital, Saint Emeric University Teaching Hospital (Reference number 3/2021). The requirement of written informed consent was waived due to the retrospective nature of the analyses.

Sources of funding

none.

Data availability statement

Data associated with our study has not been deposited into a publicly available repository, but will be made available on request.

CRediT authorship contribution statement

András Simon: Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Tamás Ámon: Project administration, Data curation. Viktória Baracsi-Botos: Project administration, Data curation. Tímea Pálfi: Project administration, Data curation. Vince Bertalan Szőke: Project administration, Data curation. Zsuzsanna Püspöki: Project administration, Data curation. Zoltán Varga: Project administration, Data curation. Loretta Zsuzsa Kiss: Writing – review & editing, Formal analysis, Data curation. Gábor Szénási: Writing – original draft, Formal analysis. Zoltán Járai: Writing – review & editing, Supervision, Project administration, Data curation. András Vereckei: Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We would like to thank László Farkas at the Makó station of the Hungarian National Ambulance Service for drawing our attention to the clockwise rotation in the chest leads as a diagnostic criterion of acute pulmonary embolism.
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References

1 Konstantinides S.V. Meyer G. Becattini C. Bueno H. Geersing G.-J. Harjola V.-P. Huisman M.V. Humbert M. Jennings C.S. Jiménez D. Kucher N. Lang I.M. Lankeit M. Lorusso R. Mazzolai L. Meneveau N. Áinle F.N. Prandoni P. Pruszczyk P. Righini M. Torbicki A. Van Belle E. Zamorano J.L. ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS) Eur. Heart J. 41 2019 543 603 2020
2 Ortel T.L. Neumann I. Ageno W. Beyth R. Clark N.P. Cuker A. Hutten B.A. Jaff M.R. Manja V. Schulman S. Thurston C. Vedantham S. Verhamme P. Witt D.M. Florez I.D. Izcovich A. Nieuwlaat R. Ross S. Sch-nemann H.J. Wiercioch W. Zhang Yuan Zhang Yuqing American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep venous thrombosis and pulmonary embolism Blood Adv 4 2020 4693 4738 33007077
3 Wells P.S. Anderson D.R. Rodger M. Ginsberg J.S. Kearon C. Gent M. Turpie A.G.G. Bormanis J. Weitz J. Chamberlain M. Bowie D. Barnes D. Hirsh J. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED d-dimer Thromb Haemost 83 2000 416 420 10744147
4 Perrier A. Desmarais S. Miron M.-J. de Moerlose P. Lepage R. Slosman D. Didier D. Unger P.-F. Patenaude J.-V. Bounameaux H. Non-invasive diagnosis of venous thromboembolism in outpatients Lancet 353 1999 190 195 9923874
5 Kruip M.J.H.A. Slob M.J. Schijen J.H.E.M. van der Heid C. Büller H.R. Use of a clinical decision rule in combination with d-dimer concentration in diagnostic workup of patients with suspected pulmonary embolism. A prospective management study Arch Int Med 162 2002 1631 1635 12123408
6 Righini M. Aujesky D. Roy P.-M. Cornuz J. de Moerlose P. Bounameaux H. Perrier A. Clinical usefulness of d-dimer depending on clinical probability and cutoff value in outpatients with suspected pulmonary embolism Arch Int Med 164 2004 2483 2487 15596640
7 Fronas S.G. Wik H.S. Dahm A.E.A. Jorgensen C.T. Gleditsch J. Raouf N. Klok F.A. Ghanima W. Safety of d-dimer testing as a stand-alone test for the exclusion of deep venous thrombosis as compared with other strategies J Thromb Haemost 16 2018 2471 2481 30303610
8 Vereckei A. Simon A. Szénási G. Katona G. Hankó L. Krix M. Szőke V.B. Baracsi Botos V. Járai Z. Masszi T. Usefulness of a novel electrocardiographic score to estimate the pre-test probability of acute pulmonary embolism Am. J. Cardiol. 130 2020 143 151 32653085
9 Douma R.A. le Gal G. Sohne M. Righini M. Kamphuisen P.W. Perrier A. Kruip M.J. Bounameaux H. Buller H.R. Roy P.M. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts BMJ 340 2010 c1415
10 Righini M. Van Es J. den Exter P.L. Roy P.M. Verschuren F. Ghuysen A. Rutschmann O.T. Sanchez O. Jaffrelot M. Trinh-Duc A. Le GallC. Moustafa F. Principe A. van Houten A.A. Ten Wolde M. Douma R.A. Hazelaar G. Erkens P.M. van Kralingen K.W. Grootenboers M.J. Durian M.F. Cheung Y.W. Meyer G. Bounameaux H. Huisman M.V. Kamphuisen P.W. Le Gal G. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study JAMA 311 2014 1117 1124 24643601
11 Linkins L.A. Takach Lapner S. Review of D-dimer testing: good, bad, and ugly Int J Lab Hematol 39 Suppl 1 2017 May 98 103 10.1111/ijlh.12665 PMID: 28447414 28447414
12 Stein P.D. Dalen J.E. McIntyre K.M. Sasahara A.A. Wenger N.K. Willis P.W. The electrocardiogram in acute pulmonary embolism Prog. Cardiovasc. Dis. 17 1975 247 257 123074
13 Madias J.E. Right ventricular dilatation: an often neglected component in the electrocardiographic assessment of patients with heart failure Europace 123 2011 1217 1218
14 Viera A.J. Garrett J.M. Understanding interobserver agreement: the kappa statistic Fam. Med. 37 2005 360 363 15883903
15 Fronas S.G. Jorgensen C.T. Dahm A.E.A. Wik H.S. Gleditsch J. Raouf N. Holst R. Klok F.A. Ghanima W. Safety of a strategy combining D-dimer testing and whole-leg ultrasonography to rule out deep vein thrombosis Blood Adv 4 2020 5002 5010 33057634
16 Logothetis C.N. Weppelmann T.A. Jordan A. Hanna C. Zhang S. Charkowick S. Oxner A. D-dimer testing for the exclusion of pulmonary embolism among hospitalized patients with COVID-19 JAMA Netw. Open 4 10 2021 e2128802 10.1001/jamanetworkopen.2021.28802
17 Geersing G.-J. Takada T. Klok F.A. Büller H.R. Courtney D.M. Freund Y. Galipienzo J. Le Gal G. Ghanima W. Klina J.A. Huisman M.V. Moons K.G.M. Perrier A. Parpia S. Robert-Ebadi H. Righini M. Roy P.-M. van Smeden M. Stals M.A.M. Wells P.S. de Wit K. Kraaijpoel N. van Es N. Ruling out pulmonary embolism across different health care settings: a systematic review and individual patient data meta-analysis PLoS Med. 19 1 2022 Jan 25 e1003905 10.1371/journal.pmed.1003905 eCollection 2022 Jan
18 Wiener R. Schwartz L. Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis Arch Int Med 171 2011 831 837 21555660
19 Righini M. Robert-Ebadi H. Diagnosis of acute pJ Thrombulmonary embolism Hämostaseologie 38 2018 11 21 29536476
20 Kahn S.R. de Wit K. Pulmonary embolism N. Engl. J. Med. 387 2022 45 57 35793208
21 Mos I.C.M. Klok F.A. Kroft L.J.M. De Roos A. Dekkers O.M. Huisman M.V. Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systemic review and meta-analysis J Thromb Haemost 7 2009 1491 1498 19552684
