a b s t r a c t

Introduction: Risk stratification of patients with acute pulmonary embolism (PE) is crucial in deciding appropriate therapy management. Blood pressure is rapidly available and a reliable parameter. We aimed to investigate BP for short-term outcome in acute PE.

Materials and methods: Data of 182 patients with acute PE were analyzed retrospectively. Logistic regression models were calculated to investigate associations between BP and in-hospital-death as well as Myocardial necrosis. Moreover, receiver operating characteristic curves and cutoff values for systolic and Diastolic BPs predicting in-hospital death and myocardial necrosis were computed.

Results: A total of 182 patients (61.5% female; mean age, 68.5 +- 15.3 years) with acute PE event were included in the study. Five patients (2.7%) died in the hospital.

Logistic regression models showed a significant association between in-hospital death and systolic BP <= 120 mm Hg (odds ratio [OR], 22.222; 95% confidence interval [CI], 2.370-200.00; P = .00660), systolic BP <= 110 mm Hg (OR, 22.727; 95% CI, 3.378-142.857; P = .00130), systolic BP <= 100 mm Hg (OR, 16.129; 95% CI, 2.304-111.111; P =

.00513), systolic BP <= 90 mm Hg (OR, 22.727; 95% CI, 3.086-166.667'; P = .00220), and diastolic BP <=65 mm Hg (OR, 14.706; 95% CI, 1.572-142.857; P = .0184), respectively. Association between myocardial necrosis and systolic BP0 N 100 mm Hg (OR, 5.444; 95% CI, 1.052-28.173; P = .0433) was also significant.

Receiver operating characteristic analysis for systolic BP predicting in-hospital death revealed an area under the curve of 0.831 with a cutoff value of 119.5 mm Hg. Receiver operating characteristic analysis for diastolic BP predicting in-hospital death showed an area under the curve of 0.903 with a cutoff value of 66.5 mm Hg.

Conclusions: Systolic and diastolic BPs are excellent Prognosis predictors of patients with acute PE. Systolic BP of 120 mm Hg or less and diastolic BP of 65 mm Hg or less at admission are connected with elevated risk of in- hospital death.

(C) 2015

1. Introduction

Abbreviations: AHA, American Heart Association; AUC, area under the curve; BP, blood pressure; CT, computed tomography; ESC, European Society of Cardiology; ICOPER, International Cooperative Pulmonary Embolism Registry; PE, pulmonary embolism; PESI, pulmonary embolism severity index; ROC, receiver operating characteristic; RVD, right ventricular dysfunction; V/Q scan, ventilation-perfusion scan.

? Conflict of interest disclosures from all authors and coauthors: None.

?? Funding: This research received no grant from any founding agency in the public,

commercial, or not-for-profit sectors.

? All authors contributed toward the study conception, design, acquisition of data,

analysis, and interpretation of data.

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

* Corresponding author at: Department of Medicine II, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany. Tel.: +49 6131 17 2995; fax: +49 6131 17 6613.

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

¹ Both authors were coshared last authors.

Current guidelines emphasise the central role of early-risk stratification of patients with an acute pulmonary embolism (PE) [1-3]. Early-risk stra- tification in acute PE event is necessary to identify PE patients with higher risk of early death, who could benefit from more intensive surveillance and especially more aggressive therapy [1,4,5]. Early-risk stratification in acute PE is crucial in deciding appropriate therapy management.

systolic and diastolic blood pressure (BP) values are rapidly avail- able and reliable parameters. It is well known that PE patients with hy- potension are at high risk for dying in short term [2,3,6] with a mortality rate greater than 15% [6,7]. However, both important Clinical scores Geneva and pulmonary embolism severity index (PESI) identified hypo- tension with systolic BP b 100 mm Hg as a significant predictor of adverse prognosis [3,8,9], whereas both the European Society of Cardiology guideline and the American Heart Association (AHA) statement recommend a systolic BP less than 90 mm Hg as a critical indicator of

http://dx.doi.org/10.1016/j.ajem.2015.07.009

0735-6757/(C) 2015

early death in acute PE [2,3]. Although the mentioned systolic BP values to predict worse outcome are not far apart, there is no general-purposed consensus about the systolic and diastolic BP cutoff values for risk stra- tification and to predict worse outcome in acute PE. In the European Society of Cardiology guidelines and AHA statement, risk stratification process of acute PE through BP values focuses on systolic BP only [2,3]. We hypothesized that the diastolic BP is at least equally important for risk stratification of acute PE than systolic and should also included in Risk stratification strategies.

The aim of our study was to investigate the systolic and diastolic BPs

for risk stratification and to predict worse outcome in acute PE and especially to calculate cutoff values to predict in-hospital death and myocardial necrosis in acute PE.

1. Methods and patients

We performed a retrospective analysis of patients with a confirmed diagnosis of acute PE, who were treated in the internal medicine depart- ment between May 2006 and June 2011. Patients with PE were identi- fied with a search in the hospital information system database for the diagnostic code of PE (International Classification of Diseases code: I26).

1. Enrolled subjects

Patients were eligible for this study

1. if the diagnosis of acute PE was confirmed by identified filling de- fect in the pulmonary artery system in computed tomography (CT) pulmonary angiogram of the chest or positive venous ultrasound/phlebography of an extremity consistent with Deep vein thrombosis in patients with Typical symptoms of PE (chest pain or dyspnea) and a detected positive D-dimer or scinti- graphic ventilation-perfusion scan read as high probability for PE;
2. if the PE patients were treated in the Internal Medicine depart- ment of the hospital; and
3. if the patients were at least 18 years old.

All CT and scintigraphic images were analyzed by experienced radi- ologists. If diagnosis of PE was not confirmed by the criteria above, the patients were not included in this study.

1. Definitions
   1. Definition of cardiac injury

Myocardial necrosis was defined as Cardiac troponin I eleva- tion greater than 0.4 ng/mL, according to the AHA scientific statement from 2011 [3].

1. Study parameters

The retrospectively analysis of the PE patients focused on BP, cardiac biomarkers, and in-hospital death.

1. Statistics

Patients with PE and with systolic BP less than 120 mm Hg were compared with PE patients with systolic BP of 120 mm Hg or greater with the help of Wilcoxon-Mann-Whitney U test as well as PE patients with systolic BP greater than 65 mm Hg compared with PE patients with systolic BP 65 mm Hg or less.

We performed logistic regression models to investigate the associa- tion between systolic as well as diastolic BP values and respectively in- hospital death and myocardial necrosis.

Receiver operating characteristic (ROC) analysis with area under the curve (AUC) for systolic and diastolic BPs predicting in-hospital death and myocardial necrosis, respectively, was computed for all PE patients

of this study, for the high-risk patients with initial systolic BP less than 90 mm Hg and for the Normotensive PE patients, respectively.

Commercially available software BIAS (version 10.04) (Epsilon Publishing House, University of Frankfurt, Germany) was used for the computerized analysis. P values less than .05 were considered statistically significant.

1. Results

Between May 2006 and June 2011, 182 patients with acute and con- firmed PE event met the inclusion criteria and were included in the study. Pulmonary embolism patients’ mean age was 68.5 +- 15.3 years (female: 70.8 +- 15.1 years; male: 64.9 +- 15.0 years). Most patients were of female sex (61.5% female, 38.5% male). Diagnosis of PE was made in 85.7% using CT, in 10.4% using ventilation-perfusion scan, and in 3.9% diagnosis made by positive venous ultrasound/phlebography of an extremity, which was consistent with DVT in patients with typical symptoms of PE (chest pain or dyspnea) and positive D-dimer level.

Of the total of 182 PE patients, 5 (2.7%) died in the hospital after the PE event.

The logistic regression models showed a significant association be- tween in-hospital death and systolic BP <= 120 mm Hg (odds ratio [OR]

, 22.222; 95% confidence interval [CI], 2.370-200.00; P = .00660), systo- lic BP <= 110 mm Hg (OR, 22.727; 95% CI, 3.378-142.857; P = .00130),

systolic BP <= 100 mm Hg (OR, 16.129; 95% CI, 2.304-111.111,; P =

.00513), systolic BP <= 90 mm Hg (OR, 22.727; 95% CI, 3.086-166.667;

P = .00220), and diastolic BP <= 65 mm Hg (OR, 14.706; 95% CI, 1.572-

142.857; P = .0184), respectively (Table 1).

Myocardial necrosis and systolic BP greater than 100 mm Hg (OR, 5.444; 95% CI, 1.052-28.173; P = .0433) were also significantly

associated (Table 2).

The calculated ROC analysis for systolic BP predicting in-hospital death revealed an AUC of 0.831 with systolic BP cutoff value of 119.5 mm Hg for all PE patients. The percentage of misclassification, sensitivity, specificity, and positive and negative predictive values were calculated as 17.3%, 81.0%, 84.5%, 85.3%, and 80.0%, respectively (Fig. 1).

Computed ROC analysis for systolic BP for prediction of in-hospital death in high-risk PE patients with initial systolic BP of b 90 mm Hg showed an AUC of 1.0 with systolic BP cutoff-value of 50.0 mm Hg. Per- centage of misclassification, sensitivity, specificity, and positive and negative predictive values were calculated as 0.0%, 100.0%, 100.0%,

100.0%, and 100.0%, respectively.

In normotensive PE patients, calculated ROC analysis for systolic BP predicating in-hospital death revealed an AUC of 0.739 with systolic BP cutoff-value of 119.5 mm Hg. Percentage of misclassification, sensi- tivity, specificity, and positive and negative predictive values were calculated as 22.8%, 72.5%, 84.5%, 87.8%, and 66.7%, respectively.

Receiver operating characteristic analysis for diastolic BP predicting in-hospital death showed an AUC of 0.903 with diastolic BP cutoff value of 66.5 mm Hg for all PE patients. The percentage of misclassification,

Table 1

Univariate logistic regression to detect the coherence of in-hospital death and systolic BP values, diastolic BP values, sex, and age

OR (95% CI)		P
Sex	0.391 (0.043-3.590)	.407
Age	1.001 (0.944-1.062)	.967
Systolic BP <= 120 mm Hg	22.222 (2.370-200.00)	.00660
Systolic BP <= 110 mm Hg	22.727 (3.378-142.857)	.00130
Systolic BP <= 100 mm Hg	16.129 (2.304-111.111)	.00513
Systolic BP <= 90 mm Hg	22.727 (3.086-166.667)	.00220
Diastolic BP <= 65 mm Hg	14.706 (1.572-142.857)	.0184
Diastolic BP <= 75 mm Hg	2.5027E + 05 (0.000-1.982E + 110)	.920
Diastolic BP <= 85 mm Hg	1.7562E + 05 (0.000-2.547E + 135)	.937
Systolic BP <= 120 mm Hg and	20.625 (3.106-136.941)	.00173

diastolic BP <= 65 mm Hg

Table 2

Univariate logistic regression to detect the coherence of myocardial necrosis and systolic BP values, diastolic BP values, sex, and age

	OR (95% CI)	P
Sex	1.291 (0.662-2.516)	.454
Age	0.981 (0.959-1.004)	.0980
Systolic BP N 120 mm Hg	1.417 (0.610-3.291)	.418
Systolic BP N 110 mm Hg	3.170 (0.880-11.417)	.0776
Systolic BP N 100 mm Hg	5.444 (1.052-28.173)	.0433
Systolic BP N 90 mm Hg	3.500 (0.615-19.935)	.158
Diastolic BP N 65 mm Hg	0.577 (0.262-1.273)	.173
Diastolic BP N 75 mm Hg	0.948 (0.497-1.807)	0.871
Diastolic BP N 85 mm Hg	0.588 (0.301-1.146)	.118

sensitivity, specificity, and positive and negative predictive values were calculated as 11.6%, 100.0%, 81.2%, 76.8%, and 100.0%, respectively

(Fig. 2).

Computed ROC analysis for systolic BP for prediction of in-hospital death in high-risk PE patients with initial systolic BP less than 90 mm Hg showed an AUC of 1.0 with diastolic BP cutoff-value of 30.0 mm Hg. Percentage of misclassification, sensitivity, specificity, and positive and negative predictive values were calculated as 0.0%, 100.0%, 100.0%, 100.0%, and 100.0%, respectively.

In normotensive PE patients, calculated ROC analysis for diastolic BP predicating in-hospital death revealed an AUC of 0.862 with systolic BP cutoff-value of 66.5 mm Hg. Percentage of misclassification, sensitivity, specificity, and positive and negative predictive values were calculated as 10.5%, 100.0%, 82.7%, 79.1%, and 100.0%, respectively.

The ROC analysis for systolic BP to predict myocardial necrosis (cTnI

N 0.4 ng/mL) revealed an AUC of 0.523 with systolic BP cutoff value of

111.5 mm Hg for all PE patients of this study. The percentage of mis- classification, sensitivity, specificity, and positive and negative predic- tive values were calculated as 45.0%, 52.8%, 75.0%, 95.0%, and 15.0%, respectively (Fig. 3).

The ROC analysis for diastolic BP to predict myocardial necrosis (cTnI N 0.4 ng/mL) showed an AUC of 0.547 with cutoff value of 85.5 mm Hg for all PE patients of this study. The percentage of misclassification, sensitivity, specificity, and positive and negative predictive values were calculated as 43.8%, 54.9%, 58.3%, 69.0%, and 43.3%, respectively (Fig. 4).

Patients with PE and with systolic BP less than 120 mm Hg at admis- sion showed a higher percentage of in-hospital death than did those with systolic BP of 120 mm Hg or greater (13.3% vs 0.7%, P =

.000108). Also, PE patients with diastolic BP of 65 mm Hg or less at

Fig. 1. Receiver operating characteristic curve with AUC and Youden index were calculated to test the effectiveness of systolic BP to predict in-hospital death in acute PE.

Fig. 2. Receiver operating characteristic curve with AUC and Youden index were calculated to test the effectiveness of diastolic BP to predict in-hospital death in acute PE.

admission revealed a higher percentage of in-hospital death than did those with diastolic BP greater than 65 mm Hg (9.3% vs 0.7%, P =

.002251; Table 3).

1. Discussion

Acute PE interferes with circulation, heart, lungs, and especially Gas exchange [2,10]. The consequence of an acute PE event is primarily he- modynamic and gets visible if more than 30% of pulmonary arterial bed is occluded by thrombus material [6]. Severe obstruction of blood flow to a lobe or multiple segments of the lung by PE thrombus material could lead to Right heart failure with insufficient maintenance of BP (hypotension) and high risk of short-term death [3,5,11]. Systolic BP less than 90 mm Hg was identified as one important prognostic factor in the International Cooperative Pulmonary Embolism Registry [12]. In the PESI and the simplified PESI, a systolic BP less than 100 mm Hg is one of the parameters to predict worse outcome [2,9,13].

Although the mentioned systolic BP values to predict worse outcome are not far apart, there is no general-purposed consensus about the sys- tolic and diastolic BP cutoff values for risk stratification and to predict worse outcome in acute PE. The objective of our study was to investigate the systolic and diastolic BPs for risk stratification and to predict worse

Fig. 3. Receiver operating characteristic curve with AUC and Youden index were calculated to test the effectiveness of systolic BP to predict myocardial necrosis in acute PE.

Fig. 4. Receiver operating characteristic curve with AUC and Youden index were calculated to test the effectiveness of diastolic BP to predict myocardial necrosis in acute PE.

outcome in acute PE. Most of the research until now focused on the role of systolic BP in acute PE. Our animus was not only to focus on systolic BP but also to investigate diastolic BP in outcome prediction and risk stratification of acute PE.

Patients with acute PE in our study sample revealed a low percent-

age (2.7%) of in-hospital death in comparison to other studies [2,14-16]. Patients with PE and with a systolic BP 120 mm Hg of less were of 22.2-fold risk to die in-hospital after acute PE event. Also, a dia- stolic BP of 65 mm Hg or less was connected with 14.7-fold risk of in- hospital death. Patients with PE and with systolic BP less than 120 mm Hg or diastolic BP of 65 mm Hg or less at admission revealed a significant higher percentage of in-hospital death than did those with higher BP values. The computed ROC analysis showed an optimal

systolic BP cutoff value of 119.5 mm Hg and an optimal diastolic BP value of 66.5 mm Hg for prediction of in-hospital death in all PE patients of our study. Effectiveness of systolic BP (AUC 0.831) and diastolic BP (AUC 0.903) to predict in-hospital death were excellent. In our study, systolic and diastolic BPs revealed a better effectiveness to predict in- hospital death than cTnI (AUC 0.719) [17]. Janata et al [18] described a higher effectiveness (AUC 0.92) for cTnT predicting in hospital death [18]. In the study of Kucher et al [19], the reported AUC for predicting adverse outcome was 0.89 for cTnI alone and AUC was 0.90 for the com- bination of cTnI in combination with right ventricular dysfunction in echocardiography [19].

Although in high-risk PE patients systolic BP values less than 50 mm Hg and diastolic BP values less than 30 mm Hg indicate for elevated risk of in-hospital death with respectively excellent effectiveness (AUC 1.0 and 1.0), in normotensive PE patients, systolic BP less than 119.5 mm Hg and diastolic BP less than 66.5 mm Hg indicate increased risk of in- hospital death with respectively good effectiveness (AUC 0.739 and 0.862).

Interestingly, PE patients with systolic BP greater than 100 mm Hg showed a 5.4-fold higher risk for myocardial necrosis (cTnI N 0.4 ng/mL) in comparison with those PE patients with a systolic BP of 100 mm Hg or less at admission. Therefore, this systolic BP behavior predicting myocardial necrosis is contrary to BP behavior for prediction of in-hospital death. Although for prediction of in-hospital death, a low BP value was connected with higher risk of in-hospital death, for predic- tion of myocardial necrosis, higher systolic BP values were associated with increased risk of myocardial necrosis. Receiver operating charac- teristic analysis for systolic BP to predict myocardial necrosis revealed an optimal systolic BP cutoff value of 111.5 mm Hg with low effective- ness (AUC 0.523). Percentage of misclassification (45.0%) and sensitivity were (52.8%) unrewarding. This could be the result of different causes of cTnI elevations. It is well known that RVD in acute PE is associated with Elevated cTnI values [17,20-23]. However, hypertensive BP values, es- pecially in cases of Hypertensive crisis, could lead to elevated cTnI values too [24,25]. The stress of dyspnea and especially chest pain in normo- tensive acute PE events might lead to hypertensive BP elevation with

Table 3

Characteristics of PE patients

Parameter	PE patients with systolic BP b 120 mm Hg at admission	PE patients with systolic BP >= 120 mm Hg at admission	P value for difference
No. of patients	30	152
Age at event (y)	67.3 +- 17.4	68.8 +- 14.8	.956
Female sex (%)	70.0	40.1	.384
Comorbidities (%)
Surgery or trauma in last 3 mo before PE event (%)	23.3	17.1	.593
DVT or PE in patient’s history (%)	23.3	23.7	.956
DVT actually (%)	70.0	65.8	.719
Cancer disease actually or in patient’s history (%)	30.0	18.4	.319
Lung infarction with pneumonia (%)	56.7	42.7	.231
In-hospital death (%)	13.3	0.7	.000108
Symptoms
Chest pain (%)	30.0	33.6	.761
Dyspnea (%)	86.7	80.3	.583
Hemoptysis (%)	0.0	3.9	.739
Syncope or collaps (%)	20.0	9.2	.354
Physical examination Systolic BP (mm Hg)	97.8 +- 26.6	152.7 +- 21.2
Diastolic BP (mm Hg)	57.8 +- 18.7	81.3 +- 17.4
Heart rate (beats/min)	101.9 +- 26.6	92.2 +- 24.2	.0244
Shock index	1.14 +- 0.64	0.62 +- 0.18	b.000001
laboratory marker
cTnI (ng/mL)	0.16 +- 0.23	0.12 +- 0.29	.339
Creatinine kinase (U/L)	81.54 +- 76.74	95.0 +- 182.5	.180
Creatinine (mg/dL)	1.09 +- 0.40	1.10 +- 0.35	.491
D-Dimer (mg/L)	1.91 +- 1.39	2.84 +- 3.88	.960
Echocardiography
Systolic pulmonary artery pressure	35.8 +- 12.6	33.6 +- 18.9	.698

Patients with PE were subdivided in group of PE patients with systolic BP less than 120 mm Hg and those with BP of at least 120 mm Hg at admission. Results were described as mean values with SD or relative percentages. Groups were compared with Wilcoxon-Mann-Whitney U test.

concomitant cTnI elevation. Therefore, low effectiveness of BP for prediction of myocardial necrosis and the divergent behavior could be explained by these facts of different causes of cTnI elevations.

Summarizing the results of our study, we found an excellent effec- tiveness of systolic and diastolic BPs to predict in-hospital death after acute PE event. These results are of peculiar interest, because systolic and diastolic BP values are rapidly available and reliable parameters, and early-risk stratification of patients with acute PE is crucial in deci- ding appropriate therapy management [1,4,5].

It is well known that PE patients with hypotension are at high risk for dying in short term [2,3,6] with a mortality rate more than 15% [6,7]. However, our study results point out that not only hypotension with systolic BP values less than 90 mm Hg [2,3] and less than 100 mm Hg [3,8,9] are significant predictors of adverse prognosis, but already systolic BP values of 120 mm Hg or less at admission are con- nected with higher rate of in-hospital death. Moreover, diastolic BP values of 65 mm Hg or less at admission are a significant prognosis pre- dictor with elevated risk of in-hospital death. The results of our study suggest that beside cTn and RVD, systolic and diastolic BP values should be included in risk stratification strategies of patients with acute PE.

1. Limitations

The most important study limitations are the small number of in- cluded PE patients, the single-center study design, and the retrospective study character. With these data, we were not able to draw conclusions about follow-up outcome. Despite these limitations, we were able to find answers to the main questions of the analysis.

1. Conclusions

Systolic and diastolic BPs are excellent prognosis predictors of pa- tients with acute PE. Systolic BP of 120 mm Hg or less and diastolic BP of 65 mm Hg or less at admission are connected with elevated risk of in-hospital death.

Risk stratification in patients with high-risk and normotensive PE beyond cTn rise and RVD should be evaluated once again in a further, larger, and properly planned study.

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