Abstract

Background: We aimed to determine the clinical, echocardiographic and hemodynamic correlates of syncope as a presenting symptom in pulmonary embolism and its impact on in-hospital and long-term outcomes.

Methods: Between July 2012 and October 2019, a total of 641 patients with PE (277 males, 364 females; median age: 65 years; range, 51 to 74 years) in whom the diagnostic work-up and risk-based management were performed according to the current pulmonary embolism guidelines were retrospectively analyzed. Clinical, laboratory and imaging data of the patients were obtained from hospital database system.

Results: Syncope was noted in 193 (30.2%) of patients on admission, and was associated with a significantly higher-risk status manifested by elevated troponin and D-dimer levels, a higher Pulmonary Embolism Severity Index scores, deterioration of right-to-left ventricular diameter ratio, right ventricular longitudinal contraction measures, the higher Qanadli score, and higher rates of thrombolytic therapies (p<0.001) and rheolytic? thrombectomy (p=0.037) therapies. In-hospital mortality (p=0.007) and minor bleeding (p<0.001) were significantly higher in syncope subgroup. Multivariate logistic regression analysis showed that higher Pulmonary Embolism Severity Index scores and right-to-left ventricular diameter ratio were independently associated with syncope, while aging and increased heart rate predicted in-hospital mortality. Malignancy and right-to-left ventricular diameter ratio at discharge, but not syncope, were independent predictors of cumulative mortality during follow-up.

Conclusion: Syncope as the presenting symptom is associated with a higher risk due to more severe obstructive pressure load and right ventricular dysfunction requiring more proactive strategies in patients with pulmonary embolism. However, with appropriate risk-based therapies, neither in-hospital mortality nor long-term mortality can be predicted by syncope.

Acute pulmonary embolism (PE) has been considered among the most important world-wide cardiovascular diseases, resulting in morbidity and mortality. Risk stratification algorithm recommended by the currently available European Society of Cardiology (ESC) PE Guidelines is based on hemodynamic status and clinical characteristics at initial assessment, right ventricular (RV) dysfunction presence as assessed by echocardiography or computed tomographic pulmonary angiography (CTPA), and elevated cardiac biomarkers indicating RV strain and myocardial injury.[1,2]

Syncope has been documented as a presenting manifestation in approximately 25% of patients with PE.[3-6] A lthough c urrent g uidelines e mphasize the importance of this presentation in risk-based in-hospital management algorithms of PE, as a result of the uncertainties regarding the prognostic impact of syncope on the early clinical course in this setting, only two out of currently available 20 risk prediction models have included the presence of syncope.[7,8] A systematic review and meta-analysis on PE series revealed that syncope was associated with a higher risk for hemodynamic deterioration and RV dysfunction on admission, and early PE-related adverse events. However, this increased risk of early mortality seemed to be more pronounced in studies consist of unselected patients, but not in those comprising normotensive subjects only.[8] Therefore, the mechanisms of the syncope in hemodynamically stable and unstable patients may be different, and these results raise the question whether syncope itself may represent the independent prediction for in-hospital outcome.[8]

In the present study, we aimed to evaluate clinical, echocardiographic, and hemodynamic correlates of syncope presence in patients with PE and to assess whether it had a prognostic impact on the in-hospital and long-term outcomes.

Methods

This single-center, retrospective study was conducted at the Department of Cardiology, Kartal Koşuyolu Heart and Research Hospital between July 2012 and October 2019. A total of 641 patients with PE (277 males, 364 females; median age: 65 years; range, 51 to 74 years) in whom the diagnosis was confirmed and risk-based management strategies were decided following the admission to emergency department of our center were included. All consecutive patients with PE who were diagnosed based on CTPA and hospitalized were included. In accordance with the 2014 and 2019 ESC PE Guidelines, a systematic work-up with CTPA, echocardiography, biomarkers, and PE severity indexes was routinely performed for risk-based management strategies.

The CTPA images were acquired at the time of admission and discharge using a 64-slice-helical computed tomography (CT) scanner (Toshiba Aquilion 64?, Toshiba Medical Systems Corp., Tokyo, Japan) and the images recorded at the time of diagnosis and discharge. A validated CT score for pulmonary artery (PA) occlusion suggested by Qanadli et al.[9] (Qanadli score, QS), RV to left-ventricle ratio (RV/LVr), right-atrial to left-atrial diameter ratio (RA/LAr) and main, left and right PA diameters were measured from CTPA images.

We retrospectively analyzed the prospectively collected pre-existing data set of PE patients who were admitted to the emergency service. The data set consists of prospectively obtained data of patients presented to emergency service with PE, including baseline characteristics. laboratory parameters, CTPA, and echocardiographic measurements were obtained from hospital database system. Patients without imaging evidence of PE were excluded.

According to the 2009 and 2018 ESC guidelines, syncope is defined as transient loss of consciousness due to brief global cerebral hypoperfusion.[10,11] We defined PE-related syncope, if syncope occurred during PE-related symptoms are present. Patients with a suspicion of traumatic syncope underwent to cranial CT to exclude intracranial events.

Troponin-T levels were measured to diagnose myocardial injury. According to the ESC guidelines, systolic blood pressure (SBP) less than 90 mmHg at initial presentation or a decline in SBP more than 40 mmHg and lasting longer than 15 min, were the parameters to define the high-risk status.[1,2] Laboratory results, imaging data and in-hospital outcome status were retrieved from the hospital database.

Data about long-term mortality were obtained from the national healthcare database and telephone visits in January 2020 and the accessible data referred to all-cause mortality. Therapies implemented to patients were documented, including intravenous fibrinolytics, catheter-directed treatments and anticoagulants. Major or minor bleeding events during hospitalization were also recorded.

Statistical analysis
Statistical analysis was performed using the R version 4.01 software (R Foundation for Statistical Computing, Vienna, Austria) with "rms" "survival", "survminer", "ggdag" and "ggplot2" packages. Continuous data were presented in median and 25th-75th interquartile range (IQR), while categorical data were presented in number and frequency. The Mann-Whitney U test was used for the continuous data comparisons and Pearson chi-square or Fisher exact tests were used for categorical data comparison. A two-tailed p value of <0.05 was considered statistically significant.

The primary outcome was in-hospital mortality. Secondary outcome was long-term mortality. Syncope before admission was used for primary and secondary outcome. We included following parameters for in-hospital all-cause mortality: age, SBP, heart rate, blood oxygen saturation (SpO2), echocardiographic PA systolic pressure (PASP), QS, presence of syncope and RV/LVr (at the time of admission). We included following parameters for long-term all-cause mortality: Age, sex, RV/LVr at discharge, syncope, SBP (at the time of admission), heart rate (at the time of admission), SpO2 (at the time of admission) and QS (at the time of admission), and malignancy. We included SBP Pulmonary Embolism Severity Index (PESI) score, QS, PASP, and RV/LVr at the time of admission for predictors of syncope. Adjustment variables were selected according to the subject matter knowledge and finally we drew a directed acyclic graph to inform regression models.

The in-hospital risk of mortality was assessed using the multivariate logistic regression models. Effects of individual exposure were reported using the odds ratio (OR) and 95% confidence interval (CI). Predictors of syncope were assessed with the multivariate logistic regression models. Effect of individual exposure was reported using OR and 95% CI. All-cause long-term mortality was displayed by using the Kaplan-Meier plot to examine the relationship between syncope groups. The multivariate Cox proportional hazard models were used to assess effect of exposure and confounders on long-term mortality. Effect of individual exposure was reported using the hazard ratio (HR) and 95% CI.

Results

The 193 (30.2%) of 641 PE patients had a history of syncope on admission. Baseline demographic and clinical characteristics are presented in Table 1.

Table 1. Clinical characteristics of patients with pulmonary embolism on admission according to the presence or absence of syncope as presenting finding

Although age, sex, and other demographic characteristics were not associated with syncope, patients presented with syncope demonstrated a higher heart rate, a lower SpO2 and SBP, a higher risk status (according to PESI score, shock index, ESC risk algorithm) and a shorter symptom duration before admission (p<0.001 for all).

Laboratory measurements, CT angiographic, and echocardiographic parameters on admission are summarized in Table 2. Patients presented with syncope had higher troponin-T and D-dimer levels on admission (p<0.001 for both of them), a lower tricuspid annular plane systolic excursion (TAPSE) (p<0.001) and tricuspid annulus systolic velocity (St) (p=0.01), and a higher PASP (p=0.01) on echocardiography, a higher thrombotic burden as assessed by QS (p<0.001), and a higher RV/LVr (p<0.001) and RA/LAr (p=0.004) on CTPA (Table 2). Furthermore, proactive therapies including intravenous tissue lasminogen activator (tPA) and rheolytic thrombectomy were more often utilized in patients presented with syncope (p<0.001 and p=0.037, respectively).

Table 2: Echocardiographic, CT angiographic and laboratory measures in acute pulmonary embolism patients with or without syncope on admission

Post-treatment differences regarding clinical, echocardiographic, and CTPA findings were also evaluated (Table 3). There were no significant differences at discharge between syncope groups in all terms including hemodynamic variables such as SBP, heart rate, SpO2 (p=0.470, p=0.514, p=0.058, respectively), TAPSE, St, PASP (p=0.264, p=0.587, and p=0.460, respectively) and CTPA measures of QS, RV/LVr and RA/LAr (p=0.770, p=0.441, and p=0.865, respectively). In-hospital mortality and minor bleeding was more observed in patients presenting with syncope (p=0.007 and p<0.001, respectively), while major bleeding events and long-term mortality were comparable between patients with or without syncope at the time of admission (p=0.06).

Table 3: Post-treatment clinical, echocardiographic and CT angiographic measures in acute pulmonary embolism patients with or without syncope

In multivariate logistic regression analysis, higher PESI score and higher RV/LVr independently predicted syncope in PE patients (OR: 1.015, 95% CI: 1.008-1.022, p<0.001 and OR: 7.508, 95% CI: 2.401-23.475, p<0.001, respectively). The PAPS, QS and SBP at the time of admission were also included in the model; however, there was not statistically significant association (Table 4).

Table 4: Predictors of syncope in patients with PE on admission

Age and heart rate (OR: 1.035, 95% CI: 1.011-1.060, p=0.004, and OR: 1.041, 95% CI: 1.018-1.070, p<0.001, respectively], but not syncope (OR: 0.655, 95% CI: 0.284-1.520, p=0.323), were found to be independent predictors for in-hospital mortality (Table 5, Figure 1).

Table 5: Predictors of in-hospital mortality in patients with PE

Figure 1: Directed acyclic graph to inform about multivariate logistic regression model (syncope was the main exposure, in-hospital mortality was the primary outcome).
RV: Right ventricle; LV: Left-ventricle; PASP: Pulmonary artery systolic pressure

Multivariate Cox proportional regression analysis was used to examine the association between the long-term mortality and mentioned nine candidate predictors (Table 6). Among variables, RV/LVr at discharge and malignancy were independently associated with long-term mortality (HR: 1.414, 95% CI: 1.02-1.946, p=0.033 and HR: 5.261, 95% CI: 2.702-10.242, p<0.001, respectively) (Figure 2). Kaplan-Meier curve showed no differences in terms of long-term survival probability between the groups (Figure 3).

Table 6: Predictors of long-term mortality in patients with PE

Figure 2: Hazard-ratio plot for long-term mortality.

Figure 3: Kaplan-Meier plot for long-term mortality between syncope groups.

Discussion

Our single-center data suggest that presence of syncope in PE relates to a higher risk, a more severe PA obstructive burden, a more deteriorated hemodynamic status and RV dysfunction which required more proactive reperfusion strategies.[11] Mohebali et al.[12] also demonstrated that syncope was associated with increased RV strain and needed to advanced treatments in PE patients. However, possibly as a result of the appropriate risk-based PE management strategies, this relationship could not be translated to in-hospital (when adjusted with multivariate analysis) and long-term mortality.

The mechanisms and clinical impact of syncope as an early risk assessment parameter remain to be established. Although PE has been reported in up to 17% of patients with a first episode of syncope not due to other causes, one-fourth of these patients had no clinical signs or symptoms consistent with PE.[6] A systematic review and meta-analysis based on data from 29 PE studies showed that syncope related to a higher frequency of hemodynamic deterioration and RV dysfunction at presentation, a higher risk of 30-day all-cause cumulative mortality and PE-related adverse outcomes.[8,13-16] The absolute risk difference (95% CI) for all-cause death was reported to be 6% (1 to 10%) in studies consisting of unselected population, while it had no impact in PE studies restricted to normotensive patients.[8,17-22] Moreover, the association between syncope and all-cause mortality seems to be stronger than for PE-related mortality. The sensitivity analyses of this meta-analysis showed that the impact of syncope was mostly supported by studies with a lower score at formal quality assessment and by retrospective studies.[8]

In our univariate analysis, syncope was associated with a shorter symptom-diagnosis interval, a higher risk status manifested by significantly elevated biomarker levels, the higher PE severity indexes, a more severe obstructive burden and RV dysfunction, and the higher utilization rates of thrombolytics and rheolytic thrombectomy as proactive reperfusion therapies.

Surgical outcomes have improved substantially in the past decades and now offer a safe and appropriate treatment option that can reduce the mortality and morbidity associated with acute PE.[23,24] Surgical pulmonary embolectomy is another alternative in selected patients, with non-surgical approaches remaining the first-line treatment in most cases.[2,23,24] The presence of thrombolytic and catheter-directed treatment options in our center has led to the primary use of non-surgical treatments. There are no patients undergoing surgical treatment in this study population.

Although, syncope was independently associated with PESI score and RV/LVr, older age and increased heart rates, but not syncope itself, predicted in-hospital mortality. In line with the findings of meta-analysis by Barco et al.,[8] our results suggest that syncope may be only a surrogate for severity of RV dysfunction and pre-existing comorbidity, rather than an independent prognostic factor.

The present study also demonstrated the independent prognostic impact of RV/LVr at discharge and malignancy for long-term mortality. These results seem to explain the importance of the persistence of asymptomatic RV dysfunction even in the normotensive patients.

This study has some limitations. The retrospective design of this study may be considered as the main limitation. Adequately sized prospective cohort studies may clarify the question whether syncope has an independent prognostic impact beyond the currently available risk criteria. Moreover, a comparison among normotensive, hypotensive and unselected PE populations might provide a comprehensive assessment for prognostic impact of syncope in this setting.

In conclusion, syncope as presenting symptom relates to a higher risk status due to a more severe obstructive burden, pressure load and right ventricular strain requiring more proactive reperfusion strategies in pulmonary embolism patients. However, with appropriate management, syncope predicts neither in-hospital, nor long-term cumulative mortality.

Ethics Committee Approval: The study protocol was approved by the Kartal Koşuyolu Heart and Research Hospital Instutional Ethics Committee (date/no: 20.10.2020/372). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patient Consent for Publication: A written informed consent was obtained from each patient.

Data Sharing Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions: Idea/concept: B.K., A.K., C.K., H.C.T., B.K.; Design: O.Y.A., A.H., B.K., H.C.T.; Control/ supervision: C.K., N.O., I.H.T., S.T.; Data collection and interpretation: B.K., B.K., A.H., S.T., S.K., I.H.T.; Literature review: C.K., A.K., B.K., O.Y.A., Writing the article: C.K., B.K., A.K., O.Y.A., Critical review: H.C.T., N.O., I.HT., S.K.; References and fundings: N.O., S.K. A.H., S.T.

Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding: The authors received no financial support for the research and/or authorship of this article.

References

1) Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033-69, 3069a-3069k.

2) Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020;41:543-603.

3) Kukla P, McIntyre WF, Koracevic G, Kutlesic-Kurtovic D, Fijorek K, Atanaskovic V, et al. Relation of atrial fibrillation and right-sided cardiac thrombus to outcomes in patients with acute pulmonary embolism. Am J Cardiol 2015;115:825-30.

4) Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: Results of a multicenter registry. Circulation 1997;96:882-8.

5) Goncalves ML, Abreu L, Marmelo B, Gil J, Antunes H, Pires MI, et al. The prognostic value of the clinical presentation with syncope in acute pulmonary thromboembolism. Eur J Heart Fail 2017;19:537-8.

6) Prandoni P, Lensing AW, Prins MH, Ciammaichella M, Perlati M, Mumoli N, et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med 2016;375:1524-31.

7) Elias A, Mallett S, Daoud-Elias M, Poggi JN, Clarke M. Prognostic models in acute pulmonary embolism: A systematic review and meta-analysis. BMJ Open 2016;6:e010324.

8) Barco S, Ende-Verhaar YM, Becattini C, Jimenez D, Lankeit M, Huisman MV, et al. Differential impact of syncope on the prognosis of patients with acute pulmonary embolism: A systematic review and meta-analysis. Eur Heart J 2018;39:4186-95.

9) Qanadli SD, El Hajjam M, Vieillard-Baron A, Joseph T, Mesurolle B, Oliva VL, et al. New CT index to quantify arterial obstruction in pulmonary embolism: Comparison with angiographic index and echocardiography. AJR Am J Roentgenol 2001;176:1415-20.

10) Brignole M, Moya A, de Lange FJ, Deharo JC, Elliott PM, Fanciulli A, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39:1883-948.

11) Kaymaz C, Akbal OY, Hakgor A, Tokgoz HC, Karagoz A, Tanboga IH, et al. A five-year, single-centre experience on ultrasound-assisted, catheter-directed thrombolysis in patients with pulmonary embolism at high risk and intermediate to high risk. EuroIntervention 2018;14:1136-43.

12) Mohebali D, Heidinger BH, Feldman SA, Matos JD, Dabreo D, McCormick I, et al. Right ventricular strain in patients with pulmonary embolism and syncope. J Thromb Thrombolysis 2020;50:157-64.

13) Task Force for the Diagnosis and Management of Syncope; European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA); Heart Failure Association (HFA); Heart Rhythm Society (HRS), Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30:2631-71.

14) de Winter MA, van Bergen EDP, Welsing PMJ, Kraaijeveld AO, Kaasjager KHAH, Nijkeuter M. The prognostic value of syncope on mortality in patients with pulmonary embolism: A systematic review and meta-analysis. Ann Emerg Med 2020;76:527-41.

15) Ploesteanu RL, Nechita AC, Andrucovici S, Delcea C, Mihu EM, Gae D, et al. Is syncope a predictor of mortality in acute pulmonary embolism? J Med Life 2019;12:15-20.

16) Lee YH, Cha SI, Shin KM, Lim JK, Yoo SS, Lee SY, et al. Clinical relevance of syncope in patients with pulmonary embolism. Thromb Res 2018;164:85-9.

17) Altınsoy B, Erboy F, Tanrıverdi H, Uygur F, Örnek T, Atalay F, et al. Syncope as a presentation of acute pulmonary embolism. Ther Clin Risk Manag 2016;12:1023-8.

18) Berghaus TM, Haeckel T, Behr W, Wehler M, von Scheidt W, Schwaiblmair M. Central thromboembolism is a possible predictor of right heart dysfunction in normotensive patients with acute pulmonary embolism. Thromb Res 2010;126:e201-5.

19) Calvo-Romero JM, Pérez-Miranda M, Bureo-Dacal P. Syncope in acute pulmonary embolism. Eur J Emerg Med 2004;11:208-9.

20) Casazza F, Becattini C, Bongarzoni A, Cuccia C, Roncon L, Favretto G, et al. Clinical features and short term outcomes of patients with acute pulmonary embolism. The Italian Pulmonary Embolism Registry (IPER). Thromb Res 2012;130:847-52.

21) Castelli R, Tarsia P, Tantardini C, Pantaleo G, Guariglia A, Porro F. Syncope in patients with pulmonary embolism: Comparison between patients with syncope as the presenting symptom of pulmonary embolism and patients with pulmonary embolism without syncope. Vasc Med 2003;8:257-61.

22) Duplyakov D, Kurakina E, Pavlova T, Khokhlunov S, Surkova E. Value of syncope in patients with high-tointermediate risk pulmonary artery embolism. Eur Heart J Acute Cardiovasc Care 2015;4:353-8.

23) Martinez Licha CR, McCurdy CM, Maldonado SM, Lee LS. Current management of acute pulmonary embolism. Ann Thorac Cardiovasc Surg 2020;26:65-71.

24) Deas DS, Keeling B. Surgical pulmonary embolectomy. Crit Care Clin 2020;36:497-504.