3.3 Incidence and risk factors of mortality
The survival rate of patients post-acute PE in the third and fifth year was 75.89% and 73.49%, respectively. Among the 200 patients with acute PE, 47 died during the follow-up period. Sixteen patients died of heart failure, 8 died of respiratory failure, 20 died of sepsis, and the causes of death of the three remaining patients were not recorded. The non-survivors tended to be younger and with permanent PE risk factors, including an underlying malignancy, liver disease, and chronic heart and lung failure. Also, the use of anticoagulants was higher in survivors compared with non-survivors. Regarding the echocardiographic parameters, only RV dilatation at the diagnosis of PE and mildly elevated PA pressure during the follow-up period were significantly different between survivors and non-survivors (Table 3).
3.4 The univariate and multivariable analyses of mortality
According to simple Cox regression, the influence of age at first PE, sex, DBP, and permanent PE risks on the prediction of the subsequent mortality was significant (Table 4). Malignancy (HR 6.68; 95% CI 3.01–14.83; P < .0001) as well as chronic heart or respiratory failure (HR 3.6; 95% CI 1.57–8.26; P = .0025) were permanent PE risk factors that increased the incidence of death. Concerning comorbidities, chronic obstructive pulmonary disease (HR 3.4; 95% CI 1.26–9.17; P = .0158), and liver disease (HR 3.43; 95% CI 1.53–7.68; P = .0027) were associated with increased mortality. Moreover, previous venous thromboembolic events (VTE) (HR 3.57; 95% CI 1.06–12.04; P = .0403) were also potential risk factors that affected mortality. Conversely, all other echocardiographic parameters – except for RV dilatation at the diagnosis of PE – failed to indicate subsequent mortality. Multivariable analysis using multiple Cox regression confirmed that only malignancy (HR 5.43; 95% CI 2.51–11.72; P < .0001) and chronic heart or respiratory failure (HR 5.64; 95% CI 2.53–12.54; P < .0001) significantly predicted subsequent mortality (Table 5). In patients with malignancies or chronic heart/lung disease, the Kaplan–Meier plot displayed a significantly worse survival compared to patients without malignancies or chronic heart/lung disease (Fig. 3).
This was the first study to investigate the incidence of CTEPH and mortality in a Taiwanese population after the diagnosis of PE. The incidence of CTEPH was 4% with the median time was 36 months after the first episode of PE. Previous studies have reported that the incidence of CTEPH after symptomatic acute PE ranges from 0.1% to 9.1%. With regard to the CTEPH incidence in some Asian countries, 1.7% and 6.1% were reported recently in China and Korea, respectively.[9,12] Several factors may affect the estimation of the incidence of CTEPH, such as selected populations, diagnostic methods, management of acute PE, and follow-up time.[5,9]
According to the current guidelines, patients with a history of venous thromboembolism who present with signs of right-sided heart failure should undergo a diagnostic evaluation for CTEPH.[8,12–14] However, early diagnosis of CTEPH – before the development of right heart failure – should be emphasized to enable early identification and intervention. Screening programs for CTEPH facilitate the detection of PH in specific at-risk populations. Nevertheless, it remains inconclusive whether screening should be conducted after acute PE, given the scant evidence.
Among the various modalities used to detect structural and functional effects of PH on the heart, transthoracic echocardiography is a non-invasive and simple screening tool. However, especially for patients with less-severe disease, false positive and false negative estimates are more frequent during transthoracic echocardiography compared with a right heart catheterization, which is the gold standard for PH diagnosis. Therefore, the ESC guidelines do not support the routine application of echocardiography for acute PE during follow-up. Conversely, it is more cost-efficient to identify patients with PE who have concomitant high risks for CTEPH.
In a recent meta-analysis which enrolled 772 PE-survivors generated a clinical prediction score for the diagnosis of CTEPH after PE. Prediction factors included patients with unprovoked PE, known hypothyroidism, symptom onset weeks before PE diagnosis, right ventricular dysfunction, and diabetes mellitus. In another study, patients who developed CTEPH tended to be older, had previous venous thromboembolic events, and more proximal PE than those without CTEPH. Other reports indicated that medical conditions associated with an increased risk of CTEPH include male gender, a history of splenectomy, cancer, ventriculoatrial shunt, chronic inflammatory disease, and an increased body mass index. Notably, in our study we also found that patients with risk factors such as unprovoked PE tended to develop CTEPH; however, most of the clinical risk factors were not associated with the subsequent diagnosis of CTEPH. Instead, echocardiographic parameters indicating RV dysfunction significantly predicted the development of CTEPH. Conversely, as we focused on the subsequent mortality post-acute PE, in multivariable Cox regression, the only clinical risk factors that significantly differentiated survivors from non-survivors were malignancy and chronic heart or respiratory failure.
Regarding the impact of low diastolic blood pressure, in the condition of geometric effects of RV enlargement and left ventricle (LV) chamber distortion in patients with CTEPH, the low LV preload, and the relative underfilling may result in the abnormal E/A ratio as well as the diastolic pressure.[17,18] Interestingly, female sex is a risk factor for the development of PAH, but the mortality rate was higher in male patients.[19,20] The sex paradox phenomenon was believed driven by the complex interaction between sex hormones and the pulmonary vasculature as well as RV dysfunction. Correspondingly, we found the same condition in these patients with poor outcomes. Also, in the International Cooperative Pulmonary Embolism Registry, patients with chronic heart failure and chronic obstructive pulmonary disease reportedly demonstrated prognostic factors. In our study, we further identified those risk factors, not only for their negative impact on outcomes of patients with PE, but also because of potential links to subsequent mortality. Similarly, patients with concomitant PE and liver disease may exhibit co-existing RV dysfunction while growing evidence supports the hypothesis that CTEPH is often misclassified as acute PE.[4,8] This reflected our findings that none of the patients diagnosed with CTEPH had a history of acute PE while CTEPH may be under-diagnosed or misclassified as acute PE. Collectively, the early screening of echocardiography may help in predicting the development of CTEPH, but the clinical risk factors decide the subsequent mortality.
4.1 Study limitations
There are some limitations to this study. First, only 4% of patients were finally diagnosed with CTEPH and this small population may attenuate the statistic power. Nevertheless, according to the studies mentioned above, the incidence of CTEPH is not as high as the other types of PH.[4,9,12] Compared with the other major CTEPH registries consisting of hundreds of patients, our study also enrolled 358 patients with PE, which is fewer than others. Notably, in this study, patients with suspected CTEPH were referred for further evaluation, including RHC and V/Q scan. However, only some patients received RHC, while some patients refused RHC. This may have resulted in under-estimation of the incidence of CTEPH. Second, as a retrospective study, the echocardiographic parameters may not be measured consistently or in sufficient detail. Given that RV hypertrophy is a marker of long-standing pulmonary hypertension, the dilated and hypertrophic RV observed at baseline may imply a subclinical CTEPH before the diagnosis of PE. Also, the changes in PA pressure between patients with and without CTEPH were insignificant. Thus, we cannot know whether patients diagnosed with acute PE may also have under-diagnosed CTEPH. In addition to RV dimension and PA pressure, other important signs that suggested PH included flattening of the interventricular septum, right ventricular outflow Doppler acceleration time, early diastolic pulmonary regurgitation velocity, and inferior cava diameter. Given the possible under-estimation of echo derived PA pressure in a chamber dilated RV, the gold standard test to diagnose CTEPH remains right heart catheterization, which was also performed in our study. In another perspective, using novel techniques, including speckle tracking, may also facilitate in early detection of RV dysfunction in patients post PE beyond the traditional echocardiography.[23,24]
Lastly, some clinical information which may be associated with CTEPH could have been missing from the medical records. Such information could include exercise, alcohol intake, high-sensitivity C-reactive protein, and depression.
4.2 Future directions
Despite the moderate incidence of CTEPH post PE, our finding suggests an urgent need to increase awareness of CTEPH, especially in patients with predisposing factors, to avoid under-diagnosis and under-treatment. Screening echocardiography post PE could be a feasible method for facilitating early diagnosis of subsequent CTEPH. However, larger scale prospective studies are required to further weigh the cost-efficiency of screening programs for early detection of CTEPH.
According to our findings, post-acute PE screening of CTEPH may facilitate early diagnosis and intervention, especially for those at high risk for developing CTEPH. Though the subsequent CTEPH is associated with RV echocardiographic parameters, the mortality is mainly dependent on underlying comorbidities. Therefore, optimal risk stratifications and managements of comorbidities are also crucial to improve patients’ outcomes.
Conceptualization: Chih-Hsin Hsu, Wei-Ting Li.
Data curation: Chih-Hsin Hsu, Wei-Ting Li, Hsien-Yuan Chang.
Formal analysis: Chih-Hsin Hsu, Wei-Ting Chang.
Funding acquisition: Chih-Hsin Hsu.
Investigation: Chih-Chan Lin, Hsien-Yuan Chang.
Methodology: Wei-Ting Chang.
Supervision: Chih-Hsin Hsu, Chih-Chan Lin, Wei-Ting Li, Hsien-Yuan Chang.
Validation: Chih-Chan Lin, Wei-Ting Li, Hsien-Yuan Chang, Wei-Ting Chang.
Visualization: Wei-Ting Li, Hsien-Yuan Chang, Wei-Ting Chang.
Writing – original draft: Chih-Hsin Hsu, Chih-Chan Lin, Wei-Ting Chang.
Writing – review and editing: Chih-Hsin Hsu, Wei-Ting Chang.
. Lang IM, Dorfmuller P, Vonk Noordegraaf A. The pathobiology of chronic thromboembolic pulmonary hypertension
. Ann Am Thorac Soc 2016;13: (Suppl 3): S215–21.
. Simonneau G, Torbicki A, Dorfmüller P, et al. The pathophysiology of chronic thromboembolic pulmonary hypertension
. Eur Respir Rev 2017;26:143.
. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol 2009;54: (Suppl): S67–77.
. Lang IM, Pesavento R, Bonderman D, et al. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension
: a current understanding. Eur Respir J 2013;41:462–8.
. Ende-Verhaar YM, Cannegieter SC, Vonk Noordegraaf A, et al. Incidence of chronic thromboembolic pulmonary hypertension
after acute pulmonary embolism
: a contemporary view of the published literature. Eur Respir J 2017;49:1601792.
. Guérin L, Couturaud F, Parent F, et al. Prevalence of chronic thromboembolic pulmonary hypertension
after acute pulmonary embolism
. Prevalence of CTEPH after pulmonary embolism
. Thromb Haemost 2014;112:598–605.
. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension
after pulmonary embolism
. N Engl J Med 2004;350:2257–64.
. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol 2016;69:177.
. Yang S, Yang Y, Zhai Z, et al. Incidence and risk factors of chronic thromboembolic pulmonary hypertension
in patients after acute pulmonary embolism
. J Thorac Dis 2015;7:1927–38.
. Giuliani L, Piccinino C, D’Armini MA, et al. Prevalence of undiagnosed chronic thromboembolic pulmonary hypertension
after pulmonary embolism
. Blood Coagul Fibrinolysis 2014;25:649–53.
. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;685–713:786–8.
. Park JS, Ahn J, Choi JH, et al. The predictive value of echocardiography for chronic thromboembolic pulmonary hypertension
after acute pulmonary embolism
in Korea. Korean J Intern Med 2017;32:85–94.
. Kim NH, Lang IM. Risk factors for chronic thromboembolic pulmonary hypertension
. Eur Respir Rev 2012;21:27–31.
. Bonderman D, Wilkens H, Wakounig S, et al. Risk factors for chronic thromboembolic pulmonary hypertension
. Eur Respir J 2009;33:325–31.
. D’Alto M, Romeo E, Argiento P, et al. Accuracy and precision of echocardiography versus right heart catheterization for the assessment of pulmonary hypertension. Int J Cardiol 2013;168:4058–62.
. Klok FA, Dzikowska-Diduch O, Kostrubiec M, et al. Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension
after acute pulmonary embolism
. J Thromb Haemost 2016;14:121–8.
. Mahmud E, Raisinghani A, Hassankhani A, et al. Correlation of left ventricular diastolic filling characteristics with right ventricular overload and pulmonary artery pressure in chronic thromboembolic pulmonary hypertension
. J Am Coll Cardiol 2002;40:318–24.
. Gurudevan SV, Malouf PJ, Auger WR, et al. Abnormal left ventricular diastolic filling in chronic thromboembolic pulmonary hypertension
: true diastolic dysfunction or left ventricular underfilling? J Am Coll Cardiol 2007;49:1334–9.
. Chang WT, Weng SF, Hsu CH, et al. Prognostic factors in patients with pulmonary hypertension – a nationwide cohort study. J Am Heart Assoc 2016;5:e003579.
. Lahm T, Tuder RM, Petrache I. Progress in solving the sex hormone paradox in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2014;307:L7–26.
. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism
: clinical outcomes in the International Cooperative Pulmonary Embolism
Registry (ICOPER). Lancet 1999;9162:1386–9.
. Klok FA, Delcroix M, Bogaard HJ. Chronic thromboembolic pulmonary hypertension
from the perspective of patients with pulmonary embolism
. J Thromb Haemost 2018;16:1040–51.
. Li AL, Zhai ZG, Zhai YN, et al. The value of speckle-tracking echocardiography in identifying right heart dysfunction in patients with chronic thromboembolic pulmonary hypertension
. Int J Cardiovasc Imaging 2018;34:1895–904.
. Patel B, Shah M, Garg L, et al. Trends in the use of echocardiography in pulmonary embolism
. Medicine 2018;97:e12104.
Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
chronic thromboembolic pulmonary hypertension; pulmonary embolism