There has been debate over how patients with pulmonary embolism (PE) can be safely selected for outpatient treatment.
There has been debate over how patients with pulmonary embolism (PE) can be safely selected for outpatient treatment.
To compare the Hestia criteria with the European Society of Cardiology (ESC) criteria for selecting low-risk patients with PE for outpatient treatment.
From 2008 to 2010, 496 patients with acute, symptomatic PE were screened and 275 treated at home and 221 treated in the hospital according to the Hestia Study protocol. The Hestia criteria were used to select patients for outpatient treatment. Right and left ventricular (RV and LV) diameters were measured on computed tomography images. RV dysfunction was defined as an RV/LV ratio > 1.0. Patients were classified according to the ESC criteria into low, intermediate and high-risk groups, based on blood pressure and RV dysfunction. During 3 months follow-up adverse events were scored.
Adverse events occurred in 22 patients (4.5%) treated in the hospital vs. none of the patients treated at home (P < 0.001). Sensitivity and negative predictive value for adverse outcome were 100% for the Hestia criteria and 96% and 99% for the ESC criteria, respectively. Of the patients treated at home according to the Hestia criteria, 35% were normotensive but had RV dysfunction and were classified as intermediate risk according to the ESC criteria. No adverse events happened in these patients treated at home.
Clinical criteria, such as the Hestia criteria, could be helpful in selecting patients, including those with RV dysfunction who have a low risk of adverse clinical outcome and could be candidates for outpatient treatment.
The presence of right ventricular (RV) dysfunction is an important predictor for short-term mortality in patients with pulmonary embolism (PE) . A substantial proportion of normotensive patients with PE have signs of RV dysfunction; proportions up to 60% have been reported [2, 3]. These patients with PE and RV dysfunction have a two to five times higher risk of short-term mortality than patients without RV dysfunction [2, 4-6].
The latest European Society of Cardiology (ESC) guidelines advise doctors to perform initial risk stratification in patients with PE to distinguish patients with a high risk of short-term mortality from those with a non-high risk (Grade IB recommendation) . High-risk patients are defined as having cardiovascular shock or persisting hypotension and they have a mortality risk > 30% . Normotensive patients are considered as non-high risk patients, with a lower risk of short-term mortality of 2–15% [9-11]. In non-high-risk patients, further risk stratification to intermediate and low-risk groups can be performed. Imaging (e.g. computed tomography (CT) or echocardiography) or laboratory markers ((NT-pro)BNP or troponins) have been proposed in distinguishing low from intermediate risk patients . Low-risk patients are defined by the absence of any signs of right ventricular (RV) dysfunction or myocardial ischemia on imaging and/or laboratory tests. These patients have a very low risk of short-term mortality of less than 1% . The ESC guidelines suggest that PE outpatient treatment could be considered only in patients with a low risk, determined by laboratory or imaging parameters . Importantly, these criteria are based on consensus and lack prospective validation in clinical practice.
Recently, many studies have been published using only clinical items to select low-risk patients for outpatient treatment, without the addition of markers for RV dysfunction or myocardial ischemia [12-14]. These studies conclude that patients selected with exclusively clinical items are at low risk of adverse events and can be treated at home. From 2008 to 2010 we performed the Hestia Study, a study on the safety of initial outpatient treatment in patients with PE . PE patients were selected for outpatient treatment with the Hestia criteria, a set of 11 clinical criteria (Table 1). The present study compared two methods for selection of patients for outpatient treatment: the Hestia criteria and the ESC criteria. The aim of this study was to describe the distribution of low, intermediate and high-risk patients (according to the ESC criteria), assessed by blood pressure combined with RV dysfunction measured on CT, and the clinical outcome among the patients treated at home or in the hospital, according to clinical criteria.
|1. Hemodynamically unstable?*|
|2. Thrombolysis or embolectomy necessary?|
|3. Active bleeding or high risk of bleeding?†|
|4. Oxygen supply to maintain oxygen saturation > 90% > 24 h?|
|5. Pulmonary embolism diagnosed during anticoagulant treatment?|
|6. Intravenous pain medication > 24 h?|
|7. Medical or social reason for treatment in the hospital > 24 h?|
|8. Creatinine clearance of less than 30 mL/min?‡|
|9. Severe liver impairment?§|
|11. Documented history of heparin-induced thrombocytopenia?|
|If one of the questions is answered with YES,|
|The patient can NOT be treated at home|
This study was a post-hoc analysis of data from the Hestia Study, a multicenter prospective cohort study performed in 12 Dutch hospitals from May 2008 till April 2010 . In this study patients with acute PE were selected for anticoagulant treatment at home according to the Hestia criteria, which are 11 clinical selection criteria based on signs and symptoms (Table 1). If none of the criteria were present the patient was included in the Hestia Study for experimental outpatient treatment. If one of the Hestia criteria was present the patient was admitted to the hospital. The patients treated in hospital were not study patients because they were not eligible for the intervention of outpatient treatment. After the study we reviewed the medical charts of the patients treated in hospital to investigate whether they had had adverse clinical outcomes within 3 months after the initial PE. The Hestia Study protocol was approved by the institutional review board of each participating hospital and all patients gave informed consent. The complete methods of the Hestia study are described elsewhere .
All patients were followed for 3 months. The outcomes of interest were clinical adverse events: PE-related mortality, resuscitation after respiratory or cardiac arrest, need for mechanical ventilation or use of inotropic agents, administration of thrombolytic drugs or surgical embolectomy . An independent adjudication committee assessed whether death was likely to be PE related based on autopsy reports and clinical reports.
Most of the patients underwent computed tomography pulmonary angiography (CTPA) to confirm the diagnosis of PE, but other imaging modalities were also allowed in the Hestia Study protocol. CTPA was performed by the CT equipment of the local hospitals. CT scanners of various vendors were used (Toshiba, Philips, Siemens and GE). Multi-slice non-ECG-gated helical CT with 4, 16 and 64-slice scanners was used with a slice thickness of 1 mm (64-slice scanners) or 2 mm (4 and 16-slice scanners). Tube voltage was 120–140 kV and tube current was 150–400 mA.
Left and right ventricle diameters were measured for calculation of the RV/LV ratios. The ventricular diameters were measured in the transverse plane at the widest points between the inner surface of the free wall and the surface of the interventricular septum (Fig. 1) . The maximum diameters could be found at different levels in the right and the left ventricle.
Right ventricular dysfunction was considered absent if the RV/LV ratio was 1.0 or less, modest RV dysfunction was defined as a ratio greater than 1.0, but less or equal to 1.5 and severe RV dysfunction was defined as a ratio greater than 1.5 .
The measuring of the ventricular diameters was performed on different post-processing workstations in standard axial views by one observer (WZ). This observer was trained and supervised by a radiologist with 11 years of experience of thoracic/cardiac CT imaging (LK). The observers were blinded to the clinical conditions of the patients and information regarding treatment at home or in the hospital. For logistic reasons, one observer (WZ) visited all 12 hospitals for measuring LV and RV diameters on the CT images. To determine reproducibility for ventricular diameter measurements, a pilot study was performed. The pilot study demonstrated good inter- and intraobserver agreement, as is described in more detail in Appendix I.
Patients were divided into three risk classes according to the ESC guidelines . Patients were considered to have low risk of mortality if they were hemodynamically stable and had no signs of RV dysfunction (RV/LV ratio ≤ 1.0). Patients were considered to be of intermediate risk if they were normotensive, but had signs of asymptomatic RV dysfunction on the CT scan (RV/LV ratio > 1.0). Patients were considered as high-risk patients if they presented to the Emergency Department in cardiovascular shock, had a systolic blood pressure lower than 100 mmHg or were classified as being hemodynamically unstable by the local physician, irrespective of RV/LV ratio.
We evaluated the clinical utility of the Hestia criteria and the ESC criteria by assessing the specific test characteristics for predicting adverse events. Differences between categorical variables were studied using the Fisher's exact test when comparing two groups and chi-squared test when comparing three groups. Continuous variables were compared using an independent samples t-test. The association between RV dysfunction/ESC risk groups and adverse clinical outcome was studied by calculating odds ratios (ORs) by logistic regression, adjusted for age, gender and cardiopulmonary co-morbidity. A two-sided P-value < 0.05 was considered to indicate a significant difference. SPSS version 17 (SPSS Inc, Chicago, IL, USA) was used for all analyses.
Overall, 530 patients with acute, symptomatic PE presented during the study; 297 patients were treated at home and 233 patients were admitted to the hospital. In 34 patients (6%) the CT parameters could not be measured, because ventilation/perfusion scan was used to diagnose PE (n = 18) or due to technical problems (n = 16). This resulted in 496 patients with CT scans available for evaluation, 275 patients treated at home and 221 treated in the hospital. Three patients treated in the hospital were lost to follow-up during the 3 months of follow-up because they lived abroad.
Baseline characteristics are described in Table 2. The mean duration of hospital admission was 7 days in the patients who were treated in the hospital.
|All patients n = 496||Home-treated patients n = 275||In-hospital patients n = 221a||P-value home vs hospital treatment|
|Age (years)||58 ± 17||55 ± 16||62 ± 17||< 0.001|
|Male sex||268 (54%)||159 (58%)||109 (49%)||0.07|
|Heart failure||13 (2.6%)||1 (0.4%)||12 (5.5%)||< 0.001|
|COPD||32 (6.5%)||10 (3.6%)||22 (10%)||0.005|
|Systolic blood pressure (mmHg)||138 ± 24||143 ± 21||134 ± 26||< 0.001|
|Diastolic blood pressure (mmHg)||82 ± 15||85 ± 14||80 ± 16||< 0.001|
|Heart rate (bpm)||91 ± 19||87 ± 15||95 ± 22||< 0.001|
|RV/LV ratio||1.1 ± 0.3||0.99 ± 0.2||1.2 ± 0.4||< 0.001|
|No RV dysfunction||271 (55%)||180 (66%)||91 (41%)||< 0.001|
|RV/LV ratio > 1||225 (45%)||95 (35%)||130 (59%)||< 0.001|
|Modest RV dysfunction||169 (34%)||84 (31%)||85 (39%)||0.070|
|Severe RV dysfunction||56 (11%)||11 (4%)||45 (20%)||< 0.001|
|< 7 days||4 (0.8%)||0||4 (1.8%)||0.038|
|< 30 days||11 (2.2%)||2 (0.7%)||9 (4.1%)||0.014|
|< 90 days||23 (4.7%)||3 (1.1%)||20 (9.2%)||< 0.001|
|PE-related mortality||5 (0.9%)||0||5 (2.3%)||0.016|
|Adverse events||22 (4.5%)||0||22 (10%)||< 0.001|
|< 7 days||18||0||18||< 0.001|
In Table 2 RV and LV parameters are presented. RV/LV ratio was lower in patients treated at home than in patients treated in the hospital (0.99 vs. 1.2, P < 0.001). In the total group of 496 patients, 225 (45%) had right ventricular dysfunction defined as an RV/LV ratio > 1.0: 34% had modest RV dysfunction (RV/LV ratio 1.0–1.5) and 11% had a severe RV dysfunction (RV/LV ratio > 1.5). A significantly lower proportion of patients treated at home had RV dysfunction compared with patients treated in the hospital (35% vs. 59%, P < 0.001). Patients treated in the hospital had a higher proportion of patients with severe RV dysfunction (20% vs. 4%, P < 0.001). None of the patients with a severe RV dysfunction who were treated at home had an adverse event.
RV dysfunction was significantly associated with adverse events. Patients with modest RV dysfunction had a six times higher risk of adverse events compared with patients without RV dysfunction (OR 5.8, 95%CI 1.1–29; P = 0.03) and patients with a severe RV dysfunction had a 47 times higher risk of adverse events compared with patients with no RV dysfunction (OR 47, 95% CI 9–238; P < 0.001). RV dysfunction was not significantly associated with all-cause mortality or with PE-related mortality.
The discriminative powers of both selection methods are underlined by a high sensitivity for adverse events: 100% (95% CI 82–100) in the Hestia criteria and 96% (95% CI 79–99) in the ESC criteria. Both methods also had a high negative predictive value: Hestia criteria 100% (95% CI 98–100) and ESC criteria 99% (95% CI 95–99). The specificity and positive predictive values were 58% (95% CI 54–63) and 10% (95% CI 7–15) for the Hestia criteria and 57% (95% CI 53–62) and 11% (95% CI 8–17) for the ESC criteria. The positive and negative likelihood ratios were 2.4 (95% CI 2.2–2.7) and 0 for the Hestia criteria and 2.2 (95% CI 2.0–2.6) and 0.06 (95% CI 0.009–0.44) for the ESC criteria. Both the Hestia criteria and the ESC criteria selected more than half of the patients as low risk and potentially eligible for outpatient treatment (55% and 54%).
Overall, 54% of patients were normotensive and had no RV dysfunction and could therefore be classified in the ESC low-risk group. In addition, 41% of patients were normotensive with RV dysfunction and classified as intermediate risk and 5% of patients were hemodynamically unstable and classified as high risk.
Of the 275 patients treated at home according to the Hestia criteria, 180 (65%) belonged to the low-risk ESC group, 95 (35%) belonged to the intermediate-risk ESC group and none to the high-risk ESC group (Fig. 2). None of the outpatients had an adverse event. Three outpatients died during 3 months of non-PE-related causes: one of intracranial bleeding (day 8) and two of end-stage pancreatic cancer (days 29 and 59).
Of the 221 patients treated in the hospital according to the Hestia criteria, 89 (40%) belonged to the low-risk ESC group, 160 (48%) belonged to the intermediate-risk group and 26 (12%) to the high-risk group. The main reasons for hospital admission due to the Hestia criteria in patients selected as low risk, according to the ESC criteria, were medical (mainly co-morbidities) or social reasons for hospital admission (51%) and need for oxygen supply to maintain adequate oxygen saturation (24%). The risks of adverse events were higher in all three risk groups treated in the hospital vs. the risks of adverse events of the patients treated at home (Fig. 2).
Our study demonstrates that the Hestia criteria and the ESC criteria both had good discriminative power to select patients with a low risk of adverse events for outpatient treatment (negative predictive values of 100% and 99%). Of note, 35% of patients treated at home in the Hestia Study had asymptomatic RV dysfunction, demonstrated by an increased RV/LV ratio at CTPA. These patients would have been excluded from outpatient treatment by the ESC criteria, but were treated at home safely in the Hestia Study, without PE-related adverse events. This study is the first to describe a group of patients with asymptomatic RV dysfunction who have been safely treated at home.
Both the Hestia criteria and the ESC criteria safely selected more than 50% of PE patients as low risk and potentially eligible for initial outpatient treatment. The Hestia criteria consist of risk markers for adverse outcome (e.g. hemodynamic status and hypoxia) combined with practical criteria to select PE patients for outpatient treatment. The Hestia criteria can be implemented in clinical care without changes. The ESC criteria, however, only consist of risk markers for adverse clinical outcome. Some patients with PE can not be treated at home for medical or social reasons unrelated to PE. Before the ESC criteria can be used in clinical practice for selection of PE patients for outpatient treatment, practical exclusion criteria have to be added. This would reduce the proportion of patients with PE treated at home to less than 50%.
Two studies have recently published a comparison between prognostic scores using only clinical items and scores using markers for right ventricular dysfunction [17, 18]. These studies compared the Pulmonary Embolism Severity Index (PESI) and the ESC model, in which RV dysfunction was assessed by echocardiography and levels of troponins were measured. Both studies demonstrated high negative predictive values of > 95% for both risk models. In the study by Vanni et al. the presence of RV dysfunction on echocardiography or elevated troponins was demonstrated to add incremental value to the PESI model, particularly in the PESI intermediate-risk patients. In our analysis we showed that Hestia low-risk patients can be treated safely at home whether they have RV dysfunction or not. The explanation for the discrepancy could be that within the Hestia criteria, in contrast to the PESI, the doctor's opinion of the medical condition of the patient is of importance in predicting the prognosis of the patient.
Both echocardiography and CT can be used to establish RV dysfunction, because both methods have a high negative predictive value of 92–99%, which is important in selecting low-risk PE patients. In this study CT was used to establish RV dysfunction. The advantage of CT over echocardiography is that it can be used as a diagnostic and prognostic method in the same procedure and is generally available.
This study also has some limitations. First, while the Hestia criteria were applied prospectively in the Hestia Study, the ESC criteria were determined in a post-hoc fashion. As a consequence, only hemodynamic status and the presence of RV dysfunction on CT scan were used to classify patients into the low, intermediate or high-risk ESC groups. In the ESC consensus document it is suggested that biomarkers of myocardial ischemia, including troponins, should be added. It is stated in the literature that the addition of troponin testing improves test characteristics . Troponins were not measured in the Hestia Study. However, because no PE-related adverse events happened in the patients treated at home, adding troponins to the selection of patients for outpatient treatment could not have increased the high negative predictive value of 100%.
Second, right and left ventricle diameters were measured by one investigator. However, the interobserver agreement in a subset of patients was good. In addition, the 45% proportion of PE patients with RV/LV ratio > 1.0 is well comparable to previous reported proportions of 38–58% [3, 21].
Third, we described a significant association between RV dysfunction and PE-related adverse events, but the confidence interval of the OR was wide and therefore firm conclusions about the magnitude of the effect should be avoided.
Fourth, although RV dysfunction was significantly associated with the occurrence of adverse events, we were unable to repeat the association between RV dysfunction and PE-related mortality described in the literature . The lack of a significant association between RV dysfunction and fatal PE is probably due to the low number of fatal PEs in our study.
What are the implications of our findings? The ESC guidelines suggest that doctors should consider PE outpatient treatment only in patients with a low risk, determined by laboratory or imaging parameters, and hospitalize those with signs of RV dysfunction. As none of the hemodynamically stable patients, with or without RV dysfunction, treated at home in the Hestia Study had a PE-related adverse event, our results strongly suggest that a proportion of patients with RV dysfunction can be pre-identified, who could be treated at home safely. Clinical criteria, such as the Hestia criteria, could be helpful in selecting patients with RV dysfunction who have a very low risk of an adverse clinical outcome and could be candidates for outpatient treatment. Ideally, prospective studies comparing the ESC criteria and the Hestia criteria are needed to corroborate our findings.
W. Zondag and M.V. Huisman had full access to all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript: M.V. Huisman, W. Zondag. Critical revision of the manuscript for important intellectual content: M.V. Huisman, W. Zondag, L.M.A. Vingerhoets, M.F. Durian, A. Dolsma, L.M. Faber, B.I. Hiddinga, H.M.A. Hofstee, A.D.M. Hoogerbrugge, M.M.C. Hovens, G. Labots, T. Vlasveld, M.J.M. de Vreede, and L.J.M. Kroft. Administrative, technical, or material support: M.V. Huisman, W. Zondag, L.M.A. Vingerhoets, M.F. Durian, A. Dolsma, L.M. Faber, B.I. Hiddinga, H.M.A. Hofstee, A.D.M. Hoogerbrugge, M.M.C. Hovens, G. Labots, T. Vlasveld, M.J.M. de Vreede, and L.J.M. Kroft. Obtained funding and study supervision: M.V. Huisman. Hestia Study Group: in addition to the authors, the following investigators have participated in this study. Bronovo Hospital, The Hague: M.J.T. Crobach. Erasmus Medical Centre, Rotterdam: M.J.H.A. Kruip. HAGA Medical Centre, The Hague: R. Valentijn, D. Creemers-Schild. Haaglanden Medical Centre, The Hague: F.H. Heyning. Medisch Spectrum Twente, Enschede: M. Eijsvogel. Leiden University Medical Centre: I.C.M. Mos. Rijnland hospital, Leiderdorp: G.J.P.M. Jonkers, M. Donker. Rijnstate Hospital, Arnhem: E.F. Ullmann, Karin A.H. Kaasjager. Spaarne Hospital, Hoofddorp: C.F. Melissant. VU Medical Centre, Amsterdam: M.H.H. Kramer. Independent adjudication committee: H. Ten Cate and K. Hamulyak, Maastricht University Medical Centre, Maastricht, the Netherlands; V. Gerdes, Slotervaart Hospital, Amsterdam, the Netherlands
This work was partially supported by an unrestricted research grant from Glaxo Smith Kline (GSK) the Netherlands BV. GSK had no influence on the design and writing of the protocol, collection of data, analysis of the study results and writing of the manuscript.
Menno V. Huisman reports having received research grants from GSK and Actelion, has given presentations and has been consulting for Bayer, Boehringer Ingelheim and Pfizer. The other authors do not report any conflicts of interest.