Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism

    Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism Karsten Keller MD, Johannes Beule MD, J¨orn Oliver Balzer MD, Wolfgang Dippold MD PII: DOI: Reference:

S0735-6757(15)00565-3 doi: 10.1016/j.ajem.2015.07.009 YAJEM 55134

To appear in:

American Journal of Emergency Medicine

Received date: Revised date: Accepted date:

3 April 2015 8 July 2015 14 July 2015

Please cite this article as: Keller Karsten, Beule Johannes, Balzer J¨orn Oliver, Dippold Wolfgang, Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism, American Journal of Emergency Medicine (2015), doi: 10.1016/j.ajem.2015.07.009

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Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism

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Short title: Keller K et al.: Blood pressure and pulmonary embolism

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Keller, Karsten, MD1,2; Beule, Johannes, MD3; Balzer, Jörn Oliver, MD4,5*; Dippold, Wolfgang, MD3* 1

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Article type: "Original Article"

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Department of Medicine II, University Medical Center Mainz (Johannes Gutenberg-University Mainz) (medical director: Univ.-Prof. Dr. med. T. Münzel) 2 Center for thrombosis and hemostasis, University Medical Center Mainz (Johannes GutenbergUniversity Mainz) (medical director: Univ.-Prof. Dr. med. U. Walter) 3 Department of internal medicine, St. Vincenz and Elisabeth Hospital Mainz (KKM) (medical director: Prof. Dr. med. W. Dippold) 4 Department of Radiology and Nuclear medicine, Catholic Clinic Mainz (KKM) (medical director: Prof. Dr. med. J.O. Balzer) 5 Department of Diagnostic and Interventional Radiology, University Clinic, Johann Wolfgang Goethe-University Frankfurt/Main *Both authors were co-shared last authors

Conflict of Interest disclosures from all authors and coauthors: None.

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Funding: None.

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

Correspondence: Dr. med. Karsten Keller MD, Department of Medicine II, University Medical Center Mainz Johannes Gutenberg-University Mainz Langenbeckstr. 1 55131 Mainz Germany Telephone: 0049-6131-17-2995; Telefax: 0049-6131-17-6613 [email protected]

Abstract: Paper: 1

words: words:

234 words 3832 words

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Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism

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Short title: Blood pressure and pulmonary embolism

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Article type: "Original Article"

Conflict of Interest disclosures from all authors and coauthors: None.

words: words:

234 words 3832 words

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Abstract: Paper:

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Funding: None.

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ACCEPTED MANUSCRIPT Key words: shock index, tachycardia, blood pressure, outcome, risk stratification, pulmonary

Abbreviations

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embolism, right ventricular dysfunction

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

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AHA

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Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism

Abstract

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Introduction

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

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Data of 182 patients with acute PE were analysed retrospectively. Logistic regression models were calculated to investigate associations between BP and in-hospital-death

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as well as myocardial necrosis. Moreover ROC curves and cut-off values for systolic

Results

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and diastolic BP predicting in-hospital death and myocardial necrosis were computed.

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182 patients (61.5%female, mean age 68.5±15.3years) with acute PE event were included in the study. 5 patients (2.7%) died in-hospital. Logistic regression models showed a significant association between in-hospital death and systolic BP≤120mmHg (OR 22.222, 95%CI 2.370-200.00, P=0.00660), ≤110mmHg (OR 22.727, 3.378-142.857, P=0.00130), ≤100mmHg (OR 16.129, 2.304-111.111, P=0.00513), ≤90mmHg (OR 22.727, 3.086-166.667, P=0.00220) and diastolic BP≤65mmHg (OR 14.706, 1.572-142.857, P=0.0184) respectively. Association between myocardial necrosis and systolic BP>100mmHg (OR 5.444, 1.052-28.173, P=0.0433) was also significant.

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ACCEPTED MANUSCRIPT ROC analysis for systolic BP predicting in-hospital death revealed an AUC of 0.831 with cut-off value of 119.5mmHg. ROC analysis for diastolic BP predicting in-hospital

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death showed an AUC of 0.903 with cut-off value of 66.5mmHg.

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Conclusions

Systolic and diastolic BP are excellent prognosis predictors of patients with acute PE.

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Systolic BP ≤120mmHg as well as diastolic BP ≤65mmHg at admission are connected

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with elevated risk of in-hospital death.

Introduction

Current guidelines emphasise the central role of early risk stratification of patients with an acute pulmonary embolism (PE) [1-3]. Early risk stratification in acute PE event is

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necessary to identify PE patients with higher risk of early death, who could benefit from

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more intensive surveillance and especially more aggressive therapy [1, 4, 5]. Early risk stratification in acute pulmonary embolism (PE) is crucial in deciding appropriate

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therapy management.

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Systolic and diastolic blood pressure (BP) values are rapidly available and reliable parameters. It is well known, that PE patients with hypotension are of high risk to die in short term [2, 3, 6] with a mortality rate of >15% [6, 7]. However, both important clinical scores Geneva and PESI identified hypotension with systolic blood pressure (BP) <100mmHg as a significant predictor of adverse prognosis [3, 8, 9], while both the ESC guideline and the AHA statement recommend a systolic BP of <90mmHg as a critical indicator of 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 cut-off values for risk stratification and to predict worse outcome in acute PE. In the ESC guidelines and AHA statement risk stratification process of acute PE through BP values focus on systolic BP only [2, 3]. We 5

ACCEPTED MANUSCRIPT hypothesised 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.

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The aim of our study was to investigate the systolic and diastolic BP for risk

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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.

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. Methods and Patients

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We performed a retrospective analysis of patients with a confirmed diagnosis of acute PE, who were treated in the Internal Medicine department between May 2006 and June 2011. PE patients were identified with a search in the hospital information system

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database for the diagnostic code of PE (ICD-Code: I26).

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Enrolled subjects

Patients were eligible for this study

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1. if the diagnosis of acute PE was confirmed by identified filling defect in the

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pulmonary artery system in computed tomography pulmonary angiogram (CT) of the chest or positive venous ultrasound/phlebography of an extremity consistent with DVT in patients with typical symptoms of PE (chest pain or dyspnoea) and a detected positive D-Dimer or scintigraphic ventilationperfusion (V/Q) scan read as high probability for PE; 2. if the PE patients were treated in the Internal Medicine department of the hospital, and 3. if the patients were at least 18 years old. All CT and scintigraphic images were analyzed by experienced radiologists. If diagnosis of PE was not confirmed by the criteria above, the patients were not included in this study. 6

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Definitions

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Definition of cardiac injury

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Myocardial necrosis was defined as cTnI elevation >0.4ng/ml, according to the AHA

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scientific statement from 2011 [3].

Study parameters

biomarkers and in-hospital death.

Statistics

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The retrospectively analysis of the PE patients focused on blood pressure, cardiac

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PE Patients with systolic BP<120mmHg were compared to PE patients with systolic

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BP≥120mmHg with the help of Wilcoxon-Mann-Whitney-U-Test as well as PE Patients with systolic BP>65mmHg compared to PE patients with systolic BP≤65mmHg.

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We performed logistic regression models to investigate the association between

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systolic as well as diastolic BP values and respectively in-hospital death and myocardial necrosis.

ROC analysis with area under the curve (AUC) for systolic and diastolic blood pressure predicting respectively in-hospital death and myocardial necrosis were computed for all PE patients of this study, for the high-risk patients with initial systolic BP<90mmHg and for the normotensive PE patients respectively. Commercially available software BIAS® (version 10.04) was used for the computerised analysis. P values of <0.05 were considered as statistically significant.

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ACCEPTED MANUSCRIPT Results Between May 2006 and June 2011, 182 patients with acute and confirmed PE event

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met the inclusion criteria and were included in the study. PE patients’ mean age was

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68.5 ± 15.3 years (female: 70.8 ± 15.1 years; male: 64.9 ± 15.0 years). The majority of patients were of female gender (61.5% female, 38.5% male). PE diagnosis was made

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in 85.7% using CT, in 10.4% V/Q scan lead to diagnosis and in 3.9% diagnosis was made by positive venous ultrasound/phlebography of an extremity, which was

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consistent with DVT in patients with typical symptoms of PE (chest pain or dyspnoea) and positive D-dimer level.

Of the total of 182 PE patients, 5 (2.7%) died an in-hospital death after the PE event. The logistic regression models showed a significant association between in-hospital

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death and systolic BP≤120mmHg (OR 22.222, 95% CI 2.370-200.00, P=0.00660),

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systolic BP≤110mmHg (OR 22.727, 95% CI 3.378-142.857, P=0.00130), systolic BP≤100mmHg (OR 16.129, 95% CI 2.304-111.111, P=0.00513), systolic BP≤90mmHg

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(OR 22.727, 95% CI 3.086-166.667, P=0.00220) and diastolic BP≤65mmHg (OR

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14.706, 95% CI 1.572-142.857, P=0.0184) respectively (Table 1). Myocardial necrosis and systolic BP>100mmHg (OR 5.444, 95% CI 1.052-28.173, P=0.0433) 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 cut-off value of 119.5mmHg for all PE patients. The percentage of misclassification, sensitivity, specificity, positive and negative predictive values were calculated as 17.3%, 81.0%, 84.5%, 85.3% and 80.0% respectively (Figure 1). Computed ROC analysis for systolic BP for prediction of in-hospital death in high-risk PE patients with initial systolic BP of <90mmHg showed an AUC of 1.0 with systolic BP value of 50.0mmHg. Percentage of misclassification, sensitivity, specificity, positive and 8

ACCEPTED MANUSCRIPT negative predictive values were calculated as 0.0%, 100.0%, 100.0%, 100.0% and 100.0% respectively.

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In normotensive PE patients, calculated ROC analysis for systolic BP prediciting in-

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hospital death revealed an AUC of 0.739 with systolic BP value of 119.5mmHg. Percentage of misclassification, sensitivity, specificity, positive and negative predictive

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values were calculated as 22.8%, 72.5%, 84.5%, 87.8% and 66.7% respectively. ROC analysis for diastolic BP predicting in-hospital death showed an AUC of 0.903

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with diastolic BP cut-off value of 66.5mmHg for all PE patients. The percentage of misclassification, sensitivity, specificity, positive and negative predictive values were calculated as 11.6%, 100.0%, 81.2%, 76.8% and 100.0% respectively (Figure 2). Computed ROC analysis for systolic BP for prediction of in-hospital death in high-risk

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PE patients with initial systolic BP of <90mmHg showed an AUC of 1.0 with diastolic

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BP value of 30.0mmHg. Percentage of misclassification, sensitivity, specificity, positive and negative predictive values were calculated as 0.0%, 100.0%, 100.0%, 100.0% and

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100.0% respectively.

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In normotensive PE patients, calculated ROC analysis for diastolic BP prediciting inhospital death revealed an AUC of 0.862 with systolic BP value of 66.5mmHg. Percentage of misclassification, sensitivity, specificity, 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>0.4ng/ml) revealed an AUC of 0.523 with systolic BP cut-off value of 111.5mmHg for all PE Patients of this study. The percentage of misclassification, sensitivity, specificity, positive and negative predictive values were calculated as 45.0%, 52.8%, 75.0%, 95.0% and 15.0% respectively (Figure 3). ROC analysis for diastolic BP to predict myocardial necrosis (cTnI>0.4ng/ml) showed an AUC of 0.547 with cut-off value of 85.5mmHg for all PE patients of this study. The 9

ACCEPTED MANUSCRIPT percentage of misclassification, sensitivity, specificity, positive and negative predictive values were calculated as 43.8%, 54.9%, 58.3%, 69.0% and 43.3% respectively

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(Figure 4).

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PE patients with systolic BP <120mmHg at admission showed a higher percentage of in-hospital death than those with systolic BP ≥120mmHg (13.3% vs. 0.7%,

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P=0.000108). Also PE patients with diastolic BP ≤65mmHg at admission revealed a higher percentage of in-hospital death than those with diastolic BP >65mmHg (9.3% vs.

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0.7%, P=0.002251) (Table 3).

Discussion

Acute PE interferes with circulation, heart, lungs and especially gas exchange [2, 10].

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The consequence of an acute PE event is primarily hemodynamic and gets visible if

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>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

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material could lead to right heart failure with insufficient maintenance of BP

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(hypotension) and high risk of short term death [3, 5, 11]. Systolic BP of <90 mmHg was identified as one important prognostic factor in the International Cooperative Pulmonary Embolism Registry (ICOPER) [12]. In the pulmonary embolism severity index (PESI) and the simplified PESI a systolic BP of <100 mmHg 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 systolic and diastolic BP cut-off values for risk stratification and to predict worse outcome in acute PE. The objective of our study was to investigate the systolic and diastolic BP for risk stratification and to predict worse outcome in acute PE. Most of the research until now focussed on the role of systolic blood pressure in acute PE. Our animus was not only to focus on systolic BP 10

ACCEPTED MANUSCRIPT but also to investigate diastolic BP in outcome prediction and risk stratification of acute PE.

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Patients with acute PE in our study sample revealed a low percentage (2.7%) of in-

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hospital death in comparison to other studies [2, 14-16]. PE patients with systolic BP ≤120mmHg were of 22.2-fold risk to die in-hospital after acute PE event. Also a

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diastolic BP of ≤65mmHg was connected with 14.7-fold risk of in-hospital death. PE patients with systolic BP <120mmHg or diastolic BP ≤65mmHg at admission revealed a

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significant higher percentage of in-hospital death than those with higher BP values. The computed ROC analysis showed an optimal systolic BP cut-off value of 119.5mmHg and an optimal diastolic BP value of 66.5mmHg for prediction of in-hospital death in all PE patients of our study. Effectiveness of systolic BP (AUC 0.831) and diastolic BP

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(AUC 0.903) to predict in-hospital death were excellent. In our study, systolic as well as

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diastolic BP 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

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predicting in hospital death [18]. In the study of Kucher et al. [19] the reported AUC for

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predicting adverse outcome was 0.89 for cTnI alone and AUC 0.90 for the combination of cTnI in combination with RVD in echocardiography [19]. While in high-risk PE patients systolic BP values of <50mmHg and diastolic BP values of <30mmHg indicate for elevated risk of in-hospital death with respectively excellent effectiveness (AUC 1.0 and 1.0), in normotensive PE patients, systolic BP of <119.5mmHg and diastolic BP of <66.5mmHg indicate for increased risk of in-hospital death with respectively good effectiveness (AUC 0.739 and 0.862). Interestingly, PE patients with systolic BP>100mmHg showed a 5.4-fold higher risk for myocardial necrosis (cTnI>0.4ng/ml) in comparison to those PE patients with systolic BP≤100mmHg at admission. Therefore, this systolic BP behaviour predicting myocardial necrosis is contrary to BP behaviour for prediction of in-hospital death. 11

ACCEPTED MANUSCRIPT While for prediction of in-hospital death a low BP value was connected with higher risk of in-hospital death, for prediction of myocardial necrosis higher systolic BP values

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were associated with increased risk of myocardial necrosis. ROC analysis for systolic

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BP to predict myocardial necrosis revealed an optimal systolic BP cut-off value of 111.5mmHg with low effectiveness (AUC 0.523). Percentage of misclassification

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(45.0%) and sensitivity were (52.8%) unrewarding. This could be the result of different causes of cTnI elevations. It is well known, that right ventricular dysfunction in acute PE

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is associated with elevated cTnI values [17, 20-23]. However, hypertensive BP values, especially in cases of hypertensive crisis, could lead to elevated cTnI values too [24, 25]. The stress of dyspnoea and especially chest pain in normotensive acute PE events might lead to hypertensive BP elevation with concomitant cTnI elevation. Therefore,

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low effectiveness of BP for prediction of myocardial necrosis and the divergent

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behaviour could be explained by these facts of different causes of cTnI elevations. Summarizing the results of our study, we found an excellent effectiveness of systolic

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and diastolic BP to predict in-hospital death after acute PE event. These results are of

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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 deciding appropriate therapy management [1, 4, 5]. It is well known, that PE patients with hypotension are of high risk to die in short term[2, 3, 6] with a mortality rate of >15% [6, 7]. However, our study results point out, that not only hypotension with systolic BP values <90mmHg [2, 3] and <100mmHg [3, 8, 9] are significant predictors of adverse prognosis, but already systolic BP values ≤120mmHg at admission are connected with higher rate of in-hospital death. Moreover diastolic BP values ≤65mmHg at admission are a significant prognosis predictor with elevated risk of in-hospital death. The results of our study suggest that, beside cTn and RVD,

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ACCEPTED MANUSCRIPT systolic and diastolic blood pressure values should be included in risk stratification strategies of patients with acute PE.

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Limitations

The most important study limitations are the small number of included PE patients, the

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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

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we were able to find answers to the main questions of the analysis.

Conclusions

Systolic and diastolic BP are excellent prognosis predictors of patients with acute PE.

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Systolic BP ≤120mmHg as well as diastolic BP ≤65mmHg at admission are connected

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with elevated risk of in-hospital death.

Risk stratification in patients with high-risk and normotensive PE beyond cTn rise and

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RVD should be evaluated once again in a further, larger and properly planned study.

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Acknowledgments

All authors contributed towards the study conception, design, acquisition of data, analysis and interpretation of data.

Funding This research received no grant from any founding agency in the public, commercial or not-for-profit sectors.

Conflicts of interests None. 13

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ACCEPTED MANUSCRIPT Table legend Table 1: Univariate logistic regression to detect the coherence of in-hospital death and systolic BP values, diastolic BP values, gender and age.

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Table 2: Univariate logistic regression to detect the coherence of myocardial necrosis and systolic BP values, diastolic BP values, gender and age.

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Table 3: PE patients‘ characteristics. PE patients were subdivided in group of PE patients with systolic blood pressure <120mmHg and those with Blood pressure ≥120mmHg at admission. Results were described as mean values with standard deviation or relative percentages. Groups were compared with Wilcoxon-MannWhitney-U-Test.

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Figure 1: Receiver Operating Characteristic (ROC) curve with area under the curve (AUC) and Youden Index were calculated to test the effectiveness of systolic blood pressure to predict in-hospital death in acute PE.

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Figure 2: Receiver Operating Characteristic (ROC) curve with area under the curve (AUC) and Youden Index were calculated to test the effectiveness of diastolic blood pressure to predict in-hospital death in acute PE.

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Figure 3: Receiver Operating Characteristic (ROC) curve with area under the curve (AUC) and Youden Index were calculated to test the effectiveness of systolic blood pressure to predict myocardial necrosis in acute PE.

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Figure 4: Receiver Operating Characteristic (ROC) curve with area under the curve (AUC) and Youden Index were calculated to test the effectiveness of diastolic blood pressure to predict myocardial necrosis in acute PE.

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OR (95% CI) 0.391 (0.043-3.590) 1.001 (0.944-1.062) 22.222 (2.370-200.00) 22.727 (3.378-142.857) 16.129 (2.304-111.111) 22.727 (3.086-166.667) 14.706 (1.572-142.857) 2.5027E+05 (0.000-1.982E+110) 1.7562E+05 (0.000-2.547E+135)

0.407 0.967 0.00660 0.00130 0.00513 0.00220 0.0184 0.920 0.937

20.625 (3.106-136.941)

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Gender Age Systolic BP≤120mmHg Systolic BP≤110mmHg Systolic BP≤100mmHg Systolic BP≤90mmHg Diastolic BP≤65mmHg Diastolic BP≤75mmHg Diastolic BP≤85mmHg Systolic BP≤120mmHg as well as diastolic BP≤65mmHg

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Table 1: Univariate logistic regression to detect the coherence of in-hospital death and systolic BP values, diastolic BP values, gender and age.

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OR (95% CI)

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Gender 1.291 (0.662-2.516) 0.454 Age 0.981 (0.959-1.004) 0.0980 Systolic BP>120mmHg 1.417 (0.610-3.291) 0.418 Systolic BP>110mmHg 3.170 (0.880-11.417) 0.0776 Systolic BP>100mmHg 5.444 (1.052-28.173) 0.0433 Systolic BP>90mmHg 3.500 (0.615-19.935) 0.158 Diastolic BP>65mmHg 0.577 (0.262-1.273) 0.173 Diastolic BP>75mmHg 0.948 (0.497-1.807) 0.871 Diastolic BP>85mmHg 0.588 (0.301-1.146) 0.118 Table 2: Univariate logistic regression to detect the coherence of myocardial necrosis and systolic BP values, diastolic BP values, gender and age.

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ACCEPTED MANUSCRIPT Parameter

PE patients with PE patients systolic BP systolic <120mmHg at ≥120mmHg admission admission 30 152 67.3±17.4years 68.8±14.8 70.0% 40.1%

with P-value BP difference at

for

AC

CE

PT

ED

MA NU

SC

RI P

T

Number of patients Age at event 0.956 Female gender 0.384 Comorbidities Surgery or trauma in 23.3% 17.1% 0.593 last 3 months before PE event DVT or PE in 23.3% 23.7% 0.956 patient’s history DVT actually 70.0% 65.8% 0.719 Cancer disease 30.0% 18.4% 0.319 actually or in patient’s history Lung infarction with 56.7% 42.7% 0.231 pneumonia In-hospital death 13.3% 0.7% 0.000108 Symptoms Chest pain 30.0% 33.6% 0.761 Dyspnoea 86.7% 80.3% 0.583 Hemoptysis 0.0% 3.9% 0.739 Syncope or collaps 20.0% 9.2% 0.354 Physical examination Systolic blood 97.8±26.6 152.7±21.2 pressure (mmHg) Diastolic blood 57.8±18.7 81.3±17.4 pressure (mmHg) Heart rate 101.9±26.6 92.2±24.2 0.0244 (beats/min) Shock index 1.14±0.64 0.62±0.18 <0.000001 Laboratory marker Cardiac Troponin I 0.16±0.23 0.12±0.29 0.339 (ng/ml) Creatinine kinase 81.54±76.74 95.0±182.5 0.180 (U/l) Creatinine (mg/dl) 1.09±0.40 1.10±0.35 0.491 D-Dimer (mg/l) 1.91±1.39 2.84±3.88 0.960 Echocardiography Systolic pulmonary 35.8±12.6 33.6±18.9 0.698 artery pressure Table 3: PE patients‘ characteristics. PE patients were subdivided in group of PE patients with systolic blood pressure <120mmHg and those with Blood pressure ≥120mmHg at admission. Results were described as mean values with standard deviation or relative percentages. Groups were compared with Wilcoxon-MannWhitney-U-Test.

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