a b s t r a c t

Background: Thrombus burden in pulmonary embolism (PE) is associated with higher D-Dimer-levels and poorer prognosis. We aimed to investigate i) the influence of right ventricular dysfunction (RVD), deep venous throm- bosis (DVT), and high-risk PE-status on D-Dimer-levels and ii) effectiveness of D-Dimer to predict RVD in normo- tensive PE patients.

Methods: Overall, 161 PE patients were analyzed retrospectively, classified in 5 subgroups of thrombus burden according to clinical indications and compared regarding D-Dimer-levels. Linear regression models were com- puted to investigate the association between D-Dimer and the groups. In hemodynamically stable PE patients, a ROC curve was calculated to assess the effectiveness of D-Dimer for predicting RVD. Results: Overall, 161 patients (60.9% females, 54.0% aged N70 years) were included in this analysis. The D-Dimer- level was associated with group-category in a univariate linear regression model (? 0.050 (95%CI 0.002-0.099), P

= .043). After adjustment for age, sex, cancer, and pneumonia in a multivariate model we observed an associa- tion between D-Dimer and group-category with borderline significance (? 0.047 (95%CI 0.002-0.096), P = .058). The Kruskal-Wallis test demonstrated that D-Dimer increased significantly with higher group-category.

In 129 normotensive patients, patients with RVD had significantly higher D-dimer values compared to those without (1.73 (1.11/3.48) vs 1.17 (0.65/2.90) mg/l, P = .049). A ROC curve showed an AUC of 0.61, gender non-specific, with calculated optimal cut-off of 1.18 mg/l. Multi-variate logistic regression model confirmed an association between D-Dimer N1.18 mg/l and RVD (OR2.721 (95%CI 1.196-6.190), P = .017).

Conclusions: Thrombus burden in PE is related to elevated D-Dimer levels, and D-Dimer values N1.18 mg/l were predictive for RVD in normotensive patients. D-Dimer levels were influenced by DVT, but not by cancer, pneumo- nia, age, or Renal impairment.

(C) 2018

Introduction

An acute pulmonary embolism (PE) is a crucial event and a cardio- vascular emergency with high morbidity and mortality [1-6]. Patholog- ically, thrombotic material (embolus) occludes partly the pulmonary ar- tery bed [1,4,6,7]. Large pulmonary artery emboli with N50% occlusion of the pulmonary vascular tree are commonly accompanied by right ventricular dysfunction and a consecutively impaired left ven- tricular filling resulting in reduction of cardiac output with arterial hy- potension and syncope/collapse [1,2,4,7-13]. These signs of

? The study was conducted in St. Vincenz and Elisabeth Hospital Mainz (KKM).

* Corresponding author at: Center for thrombosis and Hemostasis, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.

E-mail address: [email protected] (K. Keller).

¹ Both authors were co-shared last authors.

Hemodynamic compromise are connected with elevated morbidity and mortality [1-4,6,7,10-12,14-18].

D-Dimer is one of the diagnostic parameters for PE and Deep venous thrombosis [7,19,20]. Plasma D-Dimer is a degradation product of cross-linked fibrin [7,21-23] and D-Dimer values are elevated in the presence of acute clots due to the simultaneous activation of coagula- tion and fibrinolysis [7,22]. Normal D-Dimer values exclude an acute PE in Hemodynamically stable patients with high probability [7,21].

Computed tomography (CT) studies suggest that higher D-dimer levels are associated with significantly higher Clot burden in pulmonary arteries [24-26].

In addition, some study results have revealed that elevated D-Dimer levels were related to an increased mortality rate or complications [22,23,27-31]. In two previously published papers concerning our study cohort we found apparently contrary results. In the first paper no association was identified between D-Dimer and RVD among pa- tients with PE who were hemodynamically stable or un-stable [6];

https://doi.org/10.1016/j.ajem.2018.01.048

0735-6757/(C) 2018

whereas in a second paper a relationship was detected between D- Dimer and PE severity status, according to recent European Society of Cardiology (ESC) guidelines [7] in patients with PE who were hemody- namically stable [32].

To summarize these results, we hypothesized that D-Dimer levels are obviously related to clot burden in the pulmonary artery bed, but may also be affected by thrombus burden in the deep veins due to DVT. Thus, the objectives of this current study were to investigate the in- fluence of DVT, RVD, and high-risk PE status on the D-Dimer level in pa- tients with PE as well as D-Dimer level to predict RVD in normotensive

patients with PE.

Methods and patients

Consecutive patients with a confirmed diagnosis of acute PE were in- cluded in a retrospective analysis. All patients were treated at the Inter- nal Medicine Department of our hospital in the 5-year period between May 2006 and June 2011. The patients with PE were identified by a search of the hospital information system database for the diagnostic code of PE (ICD-Code: I26).

Studies in Germany involving retrospective analysis of diagnostic standard data do not require an ethics statement.

Included subjects

Patients were eligible for this study based on the following:

if the diagnosis of PE was confirmed by a detected filling defect in the pulmonary artery system on a CT pulmonary angiogram of the chest, a scintigraphic ventilation-perfusion (V/Q) scan read as high probability for PE, or positive venous ultrasound/phlebography of an extremity consistent with deep venous thrombosis (DVT) in pa- tients with Typical symptoms of PE (chest pain or dyspnoea) and positive D-dimer levels;

if patients were treated in the Internal Medicine Department of the hospital;

if patients were at least 18 years old;

if the patients had D-Dimer levels measured during the acute phase.

All CT, scintigraphic, and phlebography images were analyzed by ex- perienced radiologists.

Routine diagnostic strategy

The routine diagnostic strategy followed the recommendations of the ESC guidelines from 2008 [7]. In hemodynamically stable patients with suspected PE the CT scan was the primary diagnostic tool to con- firm PE diagnosis. In cases of impaired renal function a V/Q scan was used to make the diagnosis. In a minority of patients, especially in multi-morbid patients with suspected PE, a confirmed DVT with addi- tional typical symptoms of PE and positive D-Dimer value were consid- ered adequate to establish the diagnosis of PE. Transthoracic echocardiography and laboratory examinations of cardiac tropo- nin I (cTnI) were intended for all patients with suspected and confirmed PE, but were not performed in all patients with PE.

Definitions

Definition of cardiac injury

Myocardial injury was defined as cTnI elevation N0.4 ng/ml accord- ing to the American Heart Association (AHA) scientific statement from 2011 [33].

Definition of right ventricular dysfunction

RVD was defined according to the AHA scientific statement [33] asa quotient of right ventricular (RV) septal-lateral diameter/left ventricu- lar (LV) septal-lateral diameter N0.9 in the four-chamber view on TTE or CT [33]. Additionally, RVD was defined as RV hypokinesis and tricus- pid regurgitation or a systolic pulmonary artery pressure N30 mm Hg on TTE [33].

High-risk PE

Patients with PE with a systolic blood pressure b90 mm Hg at admis- sion were classified as high-risk PE according to the definition from the recent and current ESC guidelines [7,34] and the AHA scientific state- ment [33].

Elevated creatinine

An elevation in creatinine was defined according to gender as N1.3 mg/dl in men and N1.1 mg/dl in women.

Tachycardia

Tachycardia comprised a heart rate >=100 beats per minute.

Study outcome measures

The study outcomes were all-cause in-hospital death and occurance of RVD.

Study groups

The patients with PE in our study were classified into 5 subgroups according to suspected thrombus/embolus clot burden according to clinical indications. The lowest clot burden was expected in hemody- namically stable PE patients without both RVD and DVT. These patients were included in group 1. The second group comprised hemodynami- cally stable PE patients with DVT, but without RVD. Group 3 consisted of hemodynamically stable PE patients with RVD, but without DVT. The fourth group included hemodynamically stable PE patients with both RVD and DVT. The highest clot burden was suspected in group 5 comprising the patients with high-risk PE [7].

Statistics

We compared the 5 groups using the chi-squared test to analyze the trend between the groups for categorical variables and the Kruskal- Wallis test to compare the groups regarding the D-Dimer values. Uni- variate and multivariate (adjusted for age, sex, cancer, and pneumonia) linear regression models were provided to investigate the association between the D-Dimer values and the groups regarding increasing clot burden. Results were presented as Beta coefficients (?) and 95% confi- dence intervals (CI). We computed univariate logistic regression models in order to analyze the associations between D-Dimer and the parame- ters age N70 years, sex, creatinine elevation, VTE events in patients’ medical history, pneumonia, DVT, and cancer. Results were presented as Odds Ratios (OR) and 95%CI.

For the second part of the study, we focused on hemodynamically stable PE patients with an accurate TTE. Among these, we compared normotensive patients with and without RVD regarding D-Dimer and the outcome of in-hospital death. We computed a multivariate logistic regression model (adjusted for age, Creatinine kinase, creatinine, and tachycardia) to investigate the association between D-Dimer and RVD in these patients.

In addition, we performed receiver operating characteristic curves with areas under the curves (AUC) and Youden indices to test the effectiveness of D-Dimer values to predict RVD in TTE.

The software SPSS(R) (version 22.0; SPSS Inc., Chicago, Illinois) was used for the majority of computerized analysis. For the calculation of the ROC curve with AUC and Youden cut-off values, R version 2.14.1

(2011) (R Foundation for Statistical Computing, Vienna, Austria) was used. Only P values of b.05 (two-sided) were considered to be statisti- cally significant.

Results

In total, 182 patients with confirmed PE aged at least 18 years were enrolled for this study. Among these, 21 patients had not undergone a D-dimer measurement at the acute phase and were excluded. There- fore, 161 patients (60.9% females and 54.0% aged N70 years) were in- cluded in this analysis.

Patients’ characteristics are shown in Table 1. While the proportion of those with chest pain decreased from group 1 to group 5, in contrast dyspnoea and syncope/collapse increased together with cancer and myocardial injury.

As expected, the percentage of patients, who died while hospitalized also increased with higher group number.

The D-Dimer value was significantly associated with the group cate- gory of thrombus burden in the univariate linear regression model (?

0.050 (95%CI 0.002-0.099), P = .043). After adjustment of the multivar- iate model for age, sex, cancer, and pneumonia, the association between the D-Dimer value and the group showed a borderline significance (?

0.047 (95%CI -0.002-0.096), P = .058). In addition, the Kruskal-Wallis

test demonstrated that the D-Dimer increased significantly with a higher group number (Fig. 1). These results confirm our hypothesis: the lower the group number and therefore the suggested thrombus bur- den, the lower is the D-Dimer value.

Notably, the D-Dimer levels were not significantly influenced by age, sex, renal impairment, VTE events in patients’ medical history, pneumo- nia, or cancer (Table 2).

For the second part of our study investigating the marker D-Dimer for prediction of RVD in normotensive patients, we focused on 129 pa- tients only, who were hemodynamically stable at admittance and in whom an accurate TTE was performed during the acute phase. Among these patients, 90 (69.8%) those with PE showed an RVD in TTE. The pa- tients with RVD had significantly higher D-Dimer values in comparison to those without RVD (1.73 (1.11/3.48) vs 1.17 (0.65/2.90) mg/l, P =

.049) (Fig. 2).

The ROC curve showed an AUC of 0.61, gender non-specific, with a calculated optimal D-Dimer cut-off of 1.18 mg/l to predict an RVD (Table 3, Fig. 3).

In a multivariate logistic regression model, D-Dimer values N1.18 mg/l were associated with RVD (OR 2.721 (95%CI 1.196-6.190), P =

.017).

Fig. 1. Comparison of D-Dimer levels in the different groups.

Discussion

The key findings of our study were as follows: i) the thrombus bur- den in acute PE was associated with elevation of D-Dimer levels. ii) D- Dimer values N1.18 mg/l were predictive for RVD on TTE in normoten- sive patients with moderate effectiveness regarding prediction. iii) D- Dimer levels in acute PE were influenced by DVT, but cancer, pneumo- nia, age, and renal impairment did not have a significant impact on D- Dimer elevation.

An acute PE is primarily connected with an elevated risk of impair- ment of the lungs, the circulation, and the heart [4,34,35]. Short-term outcomes depend on the intensity of the impairments in these organs [35]. In particular, a deterioration of the hemodynamic status and cardi- ac adaptations with RVD are connected with a clear worsening of the prognosis [1,2,4,7-13].

While patients with high-risk PE can be quickly identified by blood pressure, rapid risk stratification of normotensive patients with PE and cardiac adaptations, such as RVD or myocardial injury as well as higher sPESI class, requires additional anamnesis and examinations [36]. How- ever, rapid risk stratification in acute PE is crucial for determining ap- propriate monitoring and therapy [20,37,38].

Table 1

Patient characteristics and in-hospital outcomes in the 5 groups.

	Group 1 (n = 18)	Group 2 (n = 39)	Group 3 (n = 30)	Group 4 (n = 67)	Group 5 (n = 7)	P-value for trend
Age N70 years	8 (44.4%)	16 (41.0%)	18 (60.0%)	40 (59.7%)	5 (71.4%)	.242
Female sex	13 (72.2%)	18 (46.2%)	17 (56.7%)	45 (67.2%)	5 (71.4%)	.186
Risk factor for venous thromboembolism DVT or PE in patient’s history	2 (11.8%)	8 (21.1%)	6 (20.0%)	23 (34.4%)	1 (14.3%)	.213
Surgery or trauma in the last 3 months before PE event	6 (33.3%)	8 (20.5%)	4 (13.3%)	11 (16.4%)	2 (28.6%)	.441
Cancer	3 (16.7%)	3 (7.7%)	4 (13.3%)	19 (28.4%)	3 (42.9%)	.042
Symptoms Chest pain	10 (55.6%)	14 (35.9%)	15 (50.0%)	14 (20.9%)	2 (28.6%)	.015
Dyspnoea	14 (77.8%)	24 (61.5%)	26 (86.7%)	61 (91.0%)	7 (100.0%)	.002
Hemoptysis	0 (0.0%)	1 (2.6%)	0 (0.0%)	4 (6.0%)	0 (0.0%)	.467
Syncope/collapse	2 (11.1%)	1 (2.6%)	2 (6.7%)	8 (11.9%)	3 (42.9%)	.021
Tachycardia	2 (11.1%)	6 (15.4%)	12 (40.0%)	34 (50.7%)	5 (71.4%)	b.001
laboratory markers Myocardial injury	0 (0.0%)	0 (0.0%)	17 (58.6%)	34 (55.7%)	4 (66.7%)	b.001
Creatinine elevation	3 (16.7%)	3 (7.7%)	12 (40.0%)	17 (25.4%)	2 (28.6%)	.029
Complications during In-hospital stay Pneumonia	7 (38.9%)	19 (48.7%)	15 (50.0%)	26 (38.8%)	3 (42.9%)	.790
In-hospital death	0 (0.0%)	1 (2.6%)	0 (0.0%)	0 (0.0%)	2 (28.6%)	b.001

Table 2

Influence of several parameters on D-Dimer levels in univariate logistic regression models. (P values of b 0.05 in the univariate logistic regression models were considered to be sta- tistically significant).

Table 3

D-Dimer with calculated optimal cut-offs, sensitivity, specificity, positive and negative predictive value for prediction of RVD in acute PE (P values of b 0.05 were considered to be statistically significant).

	OR (95%CI)	P-value			Value	95%CI
Age N70 years	1.012 (0.928-1.105)	.783		Men
Sex	1.038 (0.952-1.133)	.396		Sensitivity	0.85	0.66-0.96
VTE event in patient’s medical history	0.976 (0.876-1.087)	.662		Specificity	0.50	0.26-0.74
DVT	1.277 (1.044-1.562)	.017		Positive predictive value	0.72	0.53-0.86
Pneumonia	1.042 (0.954-1.138)	.358		Negative predictive value	0.69	0.39-0.91
Cancer	0.962 (0.874-1.060)	.436		Youden-cut-off in men	1.08
Creatinine elevation	1.030 (0.937-1.132)	.545	Women

The D-Dimer is one of most important diagnostic parameters for normotensive PE and DVT [7,19,20,36]. Imaging studies with CT demon- strated that higher D-dimer levels were related to significantly higher clot burden in pulmonary arteries [24-26]. In addition, some studies highlighted that elevated D-Dimer levels were related to an increased mortality rate or complications [22,23,27-31]. Because RVD is common- ly caused by larger pulmonary artery emboli with N50% occlusion of the pulmonary vascular tree [1,4,6,7], we hypothesized that high-risk PE status as well as RVD would be associated with higher thrombus burden and would provoke higher D-Dimer levels.

Our study results confirmed that larger thrombus load according to clinical indications in RVD and in high-risk PE status was associated with higher D-Dimer levels compared to those patients without high- risk status and without RVD. Additionally, D-Dimer levels were predic- tive for RVD in normotensive PE patients, although the effectiveness for this prediction was only moderate.

Thus, a relationship between D-Dimer and outcome seems to exist, as has been also mentioned in studies before [22,23,27-32]. However, the following points have to be considered in the context of D-Dimer as an outcome-predicting parameter in acute PE: although D-Dimer is highly specific for fibrin, specificity to confirm the diagnosis of DVT or PE is low [7]. A wide variety of diseases, such as cancer, inflammatory diseases, infections, necrosis, and dissection of the aorta can also in- crease the D-Dimer levels [7,22,32]. Moreover, studies demonstrated that the specificity of D-Dimer examinations for PE declines with age [7,39] probably caused by an increased number of co-morbidities [7].

Fig. 2. Comparison of the D-Dimer level of normotensive PE patients with and without RVD (box-plots with quartile 1, median, quartile 3).

Sensitivity 0.91 0.79-0.98

Specificity 0.33 0.12-0.62

Positive predictive value 0.81 0.67-0.90

Negative predictive value 0.56 0.21-0.86

Youden-cut-off in women 0.67

Gender non-specific

Sensitivity 0.73 0.61-0.82

Specificity 0.55 0.36-0.72

Positive predictive value 0.78 0.66-0.87

Negative predictive value 0.47 0.31-0.64

Youden-cut-off 1.18

An increase of D-Dimer levels with age was previously reported in the literature [40,41].

In contrast to the aforementioned literature, we could not confirm that the D-Dimer level in acute PE was significantly influenced by can- cer, pneumonia, age, and renal impairment. Only DVT had a significant impact on the D-Dimer level during the acute state; however, this find- ing in particular seems to weaken the usefulness of D-Dimer as a prog- nostic marker in acute PE. Because the embolus burden in the pulmonary artery bed determines the prognosis, the clot burden in the peripheral veins increases the level of the D-Dimer measurement and confuses the prognostic performance of this parameter regarding prognosis in acute PE.

Conclusions

The thrombus burden in acute PE is related to elevated D-Dimer levels, and D-Dimer values N1.18 mg/l were predictive for RVD on TTE in normotensive patients. D-Dimer levels in acute PE were influenced by DVT, but cancer, pneumonia, age, and renal impairment did not have a significant impact on the D-Dimer elevation.

Limitations

Important study limitations are the limited number of patients with PE included and the single center, retrospective study design. Our sin- gle-center study design with enrollment of patients in a large general hospital with only basic and regular medical care could be prone to a se- lection bias, since severe PE cases and younger patients with PE could be taken to specialist units of the university medical center, which is locat- ed nearby in the same city.

Conflicts of interest

None.

Funding

None.

Fig. 3. ROC curves for D-Dimer to predict RVD unrelated to gender (A), and for both sexes singly (B).

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