Abstract
Background
The location of thrombus in acute pulmonary embolism (PE) is a debatable prognostic factor. We compared the characteristics and outcomes of hospitalized patients with central versus peripheral PE.
Methods
This retrospective study evaluated patients with acute PE diagnosed by CT pulmonary angiography who were hospitalized between 01/01/2016 and 31/12/2022. We compared patients with central (pulmonary trunk/main pulmonary artery) and peripheral (lobar/segmental/subsegmental) PE.
Results
We studied 438 patients (median age: 63 years; PE diagnosis in the Emergency Department: 64.8%; PE peripheral in 305 patients [69.6%] and central in 133 [30.4%]). Patients with central PE had higher levels of troponin I and brain natriuretic peptide and more frequent right ventricular strain by CT pulmonary angiography/ echocardiography (72.1% versus 33.3%, p < 0.0001). PE mortality risk could be classified in 355 patients; 24.4% of the 238 patients with peripheral PE were intermediate-high/ high-risk compared with 63.3% of the 117 patients with central PE. Patients with central PE had more systemic thrombolysis (13/133 [9.8%] versus 6/305 [2.0%], p < 0.0001) and more advanced endovascular therapy (15/133 [11.3%] versus 2/305 [0.7%], p < 0.0001). All-cause hospital mortality rate was similar in patients with central and peripheral PE (5.3% and 6.6%, respectively; p = 0.61). On multivariable logistic regression analysis, central versus peripheral PE was not associated with hospital mortality (odds ratio 0.392, 95% confidence interval 0.128, 1.199).
Conclusions
The majority of patients with central PE and a minority of those with peripheral PE were classified as intermediate-high/ high-risk, however, the central thrombus location was not associated with an increased risk of mortality.
Keywords: CT pulmonary angiography, Pulmonary embolism, Venous thromboembolism, Central pulmonary embolism
Background
The prognosis of acute pulmonary embolism (PE) is dependent on several factors that include patient characteristics, and thrombus load [1–3]. The location of vascular involvement of the pulmonary arterial tree may correlate with thrombus load and hence may affect prognosis. In central PE, thrombi completely or partially occlude the main pulmonary arteries [4, 5]. In peripheral PE, the thrombi obstruct blood flow in the smaller branches of the pulmonary arteries [4, 5]. Central PE has been associated with more severe clinical disease and more unfavorable outcome than peripheral PE, [4, 6–8] and is more amenable to advanced therapy such as catheter-directed thrombolysis or thrombectomy [1]. As a result, central PE has been suggested to be used in risk assessment and in the decision making for advanced therapies [4, 8].
Nevertheless, clinical studies that evaluated the association between thrombus location in PE and clinical outcomes are relatively scarce and showed mixed outcomes [6, 9–12]. In a prospective study of 301 patients presenting to the Emergency Department with acute PE, central PE was associated with adverse clinical events (adjusted odds ratio 2.92, 95% confidence interval 1.10, 7.81) [11]. In another multicenter, prospective, observational study of 874 hemodynamically stable patients with PE, central PE was observed in 319 patients (36.5%), lobar PE in 264 (30.2%) and distal in 291 (33.2%) [12]. The mortality rate was 11.9%, 6.8% and 6.2% in patients with central, lobar, and distal emboli, respectively (p < 0.001), but the multivariate analysis did not find an association between central PE and mortality [12]. In a study of 269 patients with submassive and massive PE, 172 patients (63.9%) had central PE, and 97 (36.1%) had peripheral PE [5]. The patients had similar comorbidities except for higher prevalence of hypercoagulable state in peripheral PE [5]. Central PE was less likely to present with hypotension (32.6% vs 46.4%; p = 0.02), more likely to have right ventricular strain on echocardiography (76.7% vs 57.7%, p < 0.001) and computed tomography (58.1% vs 32.0%, p < 0.0001) and more likely to receive catheter-directed therapies (18.3% vs 3.3%; p < 0.001) [5]. Surprisingly, peripheral PE had higher 30- and 90-day all-cause mortality (18.5% vs 9.3%; p = 0.03; 25.9% vs 13.5%; p = 0.02, respectively) [5]. In the multivariable analysis, thrombus location was not associated with outcome [5].
There are significant uncertainties about the clinical significance of central versus peripheral PE and whether thrombus location should be used in risk stratification of acute PE and decision making for advanced PE therapies. The objectives of this study were to compare the characteristics, including the features of right ventricular strain, management, including the use of advanced PE therapies, and outcomes of patients with central versus peripheral PE at a tertiary-care hospital.
Methods
Setting and patients
This retrospective cohort study of adult (age ≥ 18 years) patients admitted to King Abdulaziz Medical City in Riyadh, Saudi Arabia between Jan 1, 2016, and December 31, 2022, with a diagnosis of acute PE. This hospital was a tertiary-care referral center that had > 1400 beds and several ICUs. These ICUs were staffed by a multidisciplinary team comprising intensivists, respiratory therapists, nurses, and other healthcare professionals who specialized in managing critically ill patients. The ICUs operated as closed units with 24-h, 7-day onsite coverage by board-certified critical care intensivists on a 24/7 basis [13]. The hospital had an active Interventional Radiology team that provided advanced PE therapy (catheter-directed thrombolysis and thrombectomy). During the study period, it did not have a PE response team. PE was diagnosed by multi-detector row CT pulmonary angiography (CTPA). In this study, we included patients in which PE was the reason for hospital admission or was acquired in the hospital. We excluded patients with COVID-19 at the time of PE diagnosis.
Data collection
For all eligible patients, we obtained the following data: patient demographics, patient location at PE diagnosis (Emergency Department, ICU, Ward), comorbidities (diabetes, hypertension, hyperlipidemia, chronic cardiac disease, chronic respiratory disease, chronic kidney disease, cancer, previous venous thromboembolism), hospitalization in the previous 3 months, and pertinent clinical and laboratory results on the day of PE diagnosis including those required for the calculation of simplified PESI score [14] (lowest systolic blood pressure (SBP) and oxygen saturation, highest pulse, lowest hemoglobin and platelet counts, highest value of D-dimer, brain natriuretic peptide (BNP), troponin I, and serum lactate). We also noted relevant cardiac parameters and measurements (right ventricular strain on CTPA and echocardiography, right ventricular function, dilatation and systolic pressure and left ventricular ejection fraction on echocardiography). We also noted the following management elements: anticoagulation, systemic thrombolysis (tissue plasminogen activator) with its dose, advanced endovascular therapy (catheter-directed thrombolysis and thrombectomy), surgical thrombectomy, ICU admission, oxygen therapy modality including the use of invasive mechanical ventilation and requirement for vasopressor therapy.
In this study, we defined PE as the presence of an endoluminal central filling defect partially or completely occluding a pulmonary artery on CTPA [15]. For PE description, we noted the location of the thrombus in the pulmonary vasculature as reported by the reading radiologist without further adjudication and calculated the Clot Burden Score (single subsegmental PE 1 point, single segmental PE 2 points, multiple subsegmental PE 3 points, multiple segmental PE (4 points), single lobar PE including the lingula 5 points, multiple lobar PE including the lingula 6 points, single main pulmonary artery PE 7 points, multiple main pulmonary artery PE 8 points, and saddle PE 9 points) [11]. We defined central PE as the presence of a thrombus in the main pulmonary artery, or the left or right main pulmonary artery (Clot Burden Score 7–9) and peripheral PE in the lobar, segmental, or subsegmental arteries (Clot Burden Score 1–6). We also classified PE according to the European Society of Cardiology into the following groups: low risk (SBP ≥ 90 mmHg, no right ventricular strain, normal levels of troponin I and BNP), intermediate-low risk (SBP ≥ 90 mmHg, either right ventricular strain on CTPA or echocardiography or elevated troponin I or BNP), intermediate-high risk (SBP ≥ 90 mmHg, right ventricular strain on CTPA or echocardiography (as reported by the reading radiologist or cardiologist) and elevated troponin I or BNP) or high risk (period of pulselessness or sustained (> 15 min) SBP < 90 mmHg) [2, 3]. This classification predicts mortality [2, 3, 16]. Intermediate-risk PE is commonly referred to as submassive and high-risk as massive [2, 3].
The primary outcome of this study was all-cause hospital mortality. The secondary outcomes were PE-related mortality, six-month mortality, length of hospital stay and length of ICU stay. PE-related mortality was defined as death during hospitalization that occurred due to hemodynamic decompensation or respiratory failure induced by PE, or due to a complication of PE treatment [17]. Six-month mortality was assessed by reviewing medical records for evidence of dead or alive status at six months after PE diagnosis.
Data analysis
We categorized the study patients into two groups: those with central PE and those with peripheral PE. Continuous variables were presented as medians with the first and third quartiles (Q1, Q3) and categorical variables as frequencies with percentages. We compared the continuous variables between the two study groups using Student’s t-test or Mann Whitney U test, as appropriate. We compared the categorical variables between the two study groups using the chi-square or Fisher’s exact test, as appropriate. We also assessed the diagnostic performance of thrombus location to correctly classify high-intermediate risk PE in patients without hypotension by measuring sensitivity, specificity, likelihood ratios, and positive and negative predictive values.
Multivariable logistic regression models were used to evaluate the association of central versus peripheral PE with all-cause hospital mortality and six-month mortality. The additional variables entered in the model were baseline variables that were selected based on clinical relevance. These variables were age, sex, body mass index, diabetes, hypertension, hyperlipidemia, ischemic heart disease, congestive heart failure, chronic respiratory disease, chronic kidney disease, cancer, previous venous thromboembolism, diagnosis of PE within 48 h versus > 48 h of admission, PE class (high and intermediate-high risk versus lower risk), and simplified PESI (model 1). As thrombus location in lobar arteries is considered a central PE by many clinicians and is amenable for advanced endovascular therapies, [18] the regression models were run again with central PE to include thrombus location in lobar arteries (model 2). The results of the regression were presented as odds ratio with 95% confidence intervals.
Statistical software SPSS v 15 was used for data analysis, and a two-sided p-value < 0.5 was considered statistically significant.
Results
Patient characteristics
The study included 438 patients with acute PE. Table 1 describes their characteristics. The median age was 63 years, and most patients (63.7%) were females and had chronic comorbidities such as diabetes (51.1%) and hypertension (43.8%). The diagnosis of acute PE was made while in the Emergency Department in 284 patients (64.8%) and the ward in 138 (31.5%). The median clot burden score was 4 (Q1, Q3: 2, 7).
Table 1.
Characteristics of patients
|
All patients N = 438 |
Peripheral PE N = 305 |
Central PE N = 133 |
P value | |
|---|---|---|---|---|
| Age (years), median (Q1, Q3) | 63.0 (44.0, 77.0) | 61.0 (43.0, 77.0) | 64.0 (47.0, 78.5) | 0.39* |
|
Male sex, N (%) Female sex, N (%) |
159 (36.3) 279 (63.7) |
113 (37.0) 192 (63.0) |
47 (34.6) 87 (65.4) |
0.62 |
|
BMI (kg/m2), median (Q1, Q3) Obesity 30–39.9 kg/m2 N (%) Obesity ≥ 40 kg/m2, N (%) |
29.4 (25.3, 35.0) 151 (34.6) 53 (12.1) |
28.5 (24.8, 34.0) 99 (32.5) 29 (9.5) |
31.2 (26.4, 38.3) 52 (39.4) 24 (18.2) |
0.39* 0.16 0.01 |
| Comorbid conditions, N (%) | ||||
| Any comorbidity | 327 (74.7) | 225 (73.8) | 102 (76.7) | 0.52 |
| Hypertension | 192 (43.8) | 139 (45.6) | 53 (39.8) | 0.27 |
| Diabetes | 224 (51.1) | 156 (51.1) | 68 (51.1) | 1.0 |
| Hyperlipidemia | 132 (30.1) | 92 (30.2) | 40 (30.1) | 0.99 |
| Ischemic heart disease | 39 (8.9) | 32 (10.5) | 7 (5.3) | 0.08 |
| Congestive heart failure | 33 (7.5) | 27 (8.9) | 6 (4.5) | 0.11 |
| Chronic respiratory disease | 10 (2.3) | 7 (2.3) | 3 (2.3) | 1.0 |
| Chronic kidney disease | 48 (11.0) | 432 (14.1) | 5 (3.8) | 0.001 |
| Hemodialysis | 33 (7.5) | 29 (9.5) | 4 (3.0) | 0.02 |
| Cancer | 53 (12.1) | 37 (12.1) | 16 (12.0) | 0.98 |
| Previous VTE | 54 (12.3) | 32 (10.5) | 22 (16.5) | 0.08 |
| Recent hospitalization (within 3 months), N (%) | 125 (28.5) | 89 (29.2) | 36 (27.1) | 0.65 |
| Location in hospital when PE was diagnosed, N (%) | ||||
| Emergency Department | 284 (64.8) | 202 (66.2) | 82 (61.7) | 0.20 |
| Ward | 138 (31.5) | 95 (31.1) | 43 (32.3) | |
| Intensive care unit | 16 (3.7) | 8 (2.6) | 8 (6.0) | |
| Timing of diagnosis of PE, N (%) | ||||
| within 48 h of presentation | 346 (79.0) | 237 (77.7) | 109 (82.0) | 0.32 |
| after 48 h | 92 (21.0) | 68 (22.3) | 24 (18.0) | 0.32 |
| Lowest systolic BP on the day of diagnosis (mmHg), median (Q1, Q3) | 105 (94, 117) | 106 (96, 117) | 102 (92, 116) | 0.03** |
| Patients with SBP < 90 mmHg, N (%) | 62 (14.3) | 35 (11.7) | 27 (20.0) | 0.02 |
| Simplified PESI, median (Q1, Q3) | 2 (1, 3) | 2 (1, 2.5) | 2 (1, 3) | 0.01* |
| Simplified PESI score, N (%) | ||||
| 0 | 68 (15.5) | 50 (16.4) | 18 (13.5) | |
| 1 | 119 (27.2) | 93 (30.5) | 26 (19.5) | |
| 2 | 122 (27.9) | 86 (28.2) | 36 (27.1) | 0.02 |
| 3 | 88 (20.1) | 52 (17.0) | 36 (27.1) | |
| 4 | 35 (8.0) | 19 (6.2) | 16 (12.0) | |
| 5 | 6 (1.4) | 5 (1.6) | 1 (0.8) | |
| 6 | 0 (0) | 0 (0) | 0 (0) | |
| Clot burden score, median (Q1, Q3) | 4 (2, 7) | 3 (2, 4) | 8 (7, 8) | < 0.0001* |
| RV strain on CTPA, N (%) | 105/294 (35.7) | 35/196 (17.9) | 70/98 (71.4) | < 0.0001 |
| Echocardiographic findings, N (%) | ||||
| Any RV strain*** | 50/100 (50.0) | 19/57 (33.3) | 31/43 (72.1) | < 0.0001 |
| Mild/moderate | 18/40 (45.0) | 7/15 (46.7) | 11/25 (44.0) | 0.87 |
| Severe | 22/40 (55.0) | 8/15 (53.3) | 14/25 (56.0) | 0.87 |
| Unclassified | 10/50 | 4/19 | 6/31 | |
| Any RV dilatation*** | 29/68 (42.6) | 11/26 (42.3) | 18/42 (42.8) | 0.96 |
| Mild/moderate | 20/29 (69.0) | 7/11 (63.6) | 13/18 (72.2) | 0.63 |
| Severe | 9/29 (31.0) | 4/11 (36.4) | 5/18 (27.8) | 0.63 |
| Reduction in RV function*** | 77/143 (53.8) | 35/86 (40.7) | 42/57 (73.7) | < 0.0001 |
| Mild/moderate | 42/57 (73.7) | 22/31 (71.0) | 20/26 (76.9) | 0.61 |
| Severe | 15/57 (26.3) | 9/31 (29.0) | 6/26 (23.1) | 0.61 |
| Unclassified | 20/77 | 4/35 | 16/42 | |
| Increased RV systolic pressure*** | 87/113 (77.0) | 39/62 (62.9) | 48/52 (94.1) | <0.0001 |
| Estimated pressure (mmHg), median (Q1, Q3) | 55 (45, 55) | 50 (39, 56) | 50 (39, 56) | 0.84* |
| LV ejection fraction (%), median (Q1, Q3) | 55 (55, 55) | 55 (50, 55) | 55 (55, 55) | 0.003** |
| Pertinent laboratory findings within 24 h of CTPA, median (Q1, Q3) | ||||
| Lowest hemoglobin (g/dL) | 11.9 (10.1, 13.5) | 9.8 (11.8, 13.2) | 12.6 (10.8, 13.8) | 0.004** |
| Lowest platelets × 109/L | 252 (201, 349) | 254 (203, 356) | 246 (191, 342) | 0.22** |
| Highest creatinine (µmol/L) | 71.0 (60.0, 105.0) | 70.0 (59.0, 106.5) | 74.0 (62.0, 103.5) | 0.48** |
| Highest D-Dimer (mg/L) | 4.7 (2.2, 9.1) | 3.6 (2.0, 6.5) | 8.2 (3.5, 17.0) | < 0.0001** |
| Highest troponin I (pg/ml) | 16.1 (9.0, 83.3) | 9.0 (9.0, 41.4) | 64.2 (15.3, 376.0) | < 0.0001** |
| Highest BNP (ng/L) | 25.5 (7.0, 92.3) | 18.3 (5.3, 64.6) | 49.6 (14.3, 119.9) | < 0.0001** |
| Highest lactate (mmol/L) | 1.9 (1.3, 2.8) | 1.8 (1.2, 2.7) | 2.2 (1.4, 3.1) | 0.01** |
BMI Body mass index, BNP Brain natriuretic peptide, BP Blood pressure, COPD Chronic obstructive pulmonary disease, CTPA Computed tomography pulmonary angiogram, LV Left ventricle, PE Pulmonary embolism, PESI Pulmonary embolism severity index, Q1 First quartile, Q3 Third quartile, RV Right ventricle, VTE Venous thromboembolism
*Student t test
**Mann–Whitney U test
***The denominator represents the number of patients who had the variable assessed
Peripheral PE was present in 305 patients (69.6%) and central PE in 133 (30.4%). Figure 1 describes the distribution of PE location in the study population. Patients with peripheral and central PE had similar age but more morbid obesity (body mass index > 40 kg/m2) and chronic kidney disease. Patients with central PE had higher D-dimer, troponin I, BNP and lactate levels on admission (Table 1).
Fig. 1.
Distribution of the Clot Burden Score (location of thrombi in the pulmonary arterial vasculature) in the study cohort and the associated mortality rates. The p-value for between-group differences was 0.66 for all-cause hospital mortality and 0.65 for six-month mortality
Right ventricular strain on CTPA was described in 294 patients, was present in 105 (35.7%) and was more noted in patients with central PE (71.4% versus 17.9% in patients with peripheral PE, p < 0.0001). On echocardiography, right ventricular strain was described in 100 patients, was present in 50 patients (50.0%), and was also more prevalent in patients with central PE (72.1% versus 33.3%, p < 0.0001). Among the patients with right ventricular strain, the severity of strain was similar in patients with peripheral and central PE.
Classification of PE risk
For 83 patients, PE risk could not be classified due to the absence of data on cardiac injury or right ventricular strain. Patients with peripheral PE were more likely to have absent data (67/305 [22.0%] versus 16/133 [12.0%], p = 0.02). Among the 83 patients, 63 had simplified PESI ≥ 1 with most having peripheral PE (52/63, 82.5%).
Among the 355 patients who could be classified (Table 2), 102 patients (28.7%) were low-risk, 121 (34.1%) intermediate-low risk, 70 (19.7%) intermediate-high risk, and 62 (17.5%) high-risk. Among the 238 patients with peripheral PE, 24.4% were intermediate-high or high-risk. Among the 117 patients with central PE, 63.3% were intermediate-high or high-risk.
Table 2.
Classification of patients with acute pulmonary embolism according to the mortality risk and the ability of central thrombus location on CT angiography to correctly classify intermediate-high risk pulmonary embolism
|
Peripheral PE N = 238 |
Central PE N = 117 |
P value | |
|---|---|---|---|
| Classification of PE risk, N (%) | |||
| Low risk | 91/238 (38.2) | 11/117 (9.4) | |
| Intermediate low risk | 89/238 (37.4) | 35/117 (27.4) | < 0.0001 |
| Intermediate high risk | 23/238 (9.7) | 47/117 (40.2) | |
| High risk | 35/238 (14.7) | 27/117 (23.1) | |
| Unable to classify* | 67/305 (22.0) | 16 /133 (12.0) | 0.02 |
| Diagnostic performance of central thrombus location to correctly classify PE as intermediate-high risk (analysis was performed in patients without hypotension) | |||
| Value | 95% confidence interval | ||
| Sensitivity | 67.1% | 54.9% to 77.9% | |
| Specificity | 79.7% | 73.8% to 84.7% | |
| Positive Likelihood Ratio | 3.30 | 2.43 to 4.48 | |
| Negative Likelihood Ratio | 0.41 | 0.29 to 0.58 | |
| Positive Predictive Value | 50.5% | 43.0% to 58.1% | |
| Negative Predictive Value | 88.7% | 84.8% to 91.7% | |
| Accuracy | 76.7% | 71.5% to 81.4% | |
PE Pulmonary embolism
*: lack of data needed for classification (brain natriuretic peptide, troponin I, or echocardiography)
In patients without hypotension (SBP < 90 mmHg), central PE on CTPA had a sensitivity of 67.1%, specificity of 79.7%, positive predictive value of 50.5% and negative predictive value of 88.7% to correctly classify PE as intermediate-high risk rather than lower risk PE (Table 2).
Management of patients
Key management interventions are described in Table 3. Measurement of troponin I and BNP was performed in most patients (85.4% and 74.4%, respectively) with no significant difference between patients with peripheral and central PE. An echocardiography and lower limb Doppler ultrasound were performed more commonly in patients with central PE (53.4% versus 31.5%, p < 0.0001 for echocardiography and 36.8% versus 26.9%, p = 0.04 for lower limb ultrasound). Associated deep-vein thrombosis was diagnosed in more patients with central PE.
Table 3.
Management of patients with acute PE
| Variables |
All patients N = 438 |
Peripheral PE N = 305 |
Central PE N = 133 |
P value |
|---|---|---|---|---|
| Troponin I measured, N (%) | 374 (85.4) | 257 (84.3) | 117 (88.0) | 0.31 |
| BNP measured, N (%) | 326 (74.4) | 221 (72.5) | 105 (78.9) | 0.15 |
| Echocardiography performed, N (%) | 167 (38.1) | 96 (31.5) | 71 (53.4) | < 0.0001 |
| Lower limb Doppler ultrasound, N (%) | 131 (29.9) | 82 (26.9) | 49 (36.8) | 0.04 |
| DVT present, N (%) | 51/131 (38.9) | 26/82 (31.7) | 25/49 (51.0) | 0.03 |
| Systemic anticoagulation, N (%) | 434 (99.1) | 301 (98.7) | 133 (100.0) | 0.19 |
| Systemic thrombolysis, N (%) | 19 (4.3) | 6 (2.0) | 13 (9.8) | < 0.0001 |
| 50 mg tPA | 9/19 (47.4) | 2/6 (33.3) | 7/13 (53.8) | 0.63 |
| 100 mg tPA | 10/19 (52.6) | 4/6 (66.7) | 6/ 13 (46.2) | 0.63 |
| Any endovascular treatment, N (%) | 17 (3.9) | 2 (0.7) | 15 (11.3) | < 0.0001 |
| Catheter-directed thrombolysis | 13 (3.0) | 2 (0.7) | 11 (8.3) | < 0.0001 |
| Mechanical thrombectomy | 12 (2.7) | 1 (0.3) | 11 (8.3) | < 0.0001 |
| Surgical thrombectomy, N (%) | 1 (0.2) | 0 (0) | 1 (0.8) | 0.30 |
| Inferior vena cava filter, N (%) | 29 (6.6) | 15 (4.9) | 14 (10.5) | 0.03 |
| Respiratory support on the day of diagnosis, N (%) | ||||
| Room air or simple oxygen therapy | 423 (96.6) | 296 (97.0) | 127 (95.5) | |
| Non-invasive ventilation | 8 (1.8) | 6 (2.0) | 2 (1.5) | 0.29 |
| Invasive mechanical ventilation | 7 (1.6) | 3 (1.0) | 4 (3.0) | |
| Fraction of inspired oxygen (%), median (Q1, Q3) | 21 (21, 28) | 21 (21, 28) | 24 (21, 28) | 0.003 |
| Admission to the ICU, N (%) | 110 (25.1) | 58 (19.0) | 52 (39.1) | < 0.0001 |
| Vasopressor use during hospital stay, N (%) | 32 (7.3) | 19 (6.2) | 13 (9.8) | 0.19 |
| Invasive mechanical ventilation during hospital stay, N (%) | 38 (8.7) | 23 (7.5) | 15 (11.3) | 0.20 |
BNP B-type natriuretic peptide, DVT Deep-vein thrombosis, ICU Intensive care unit, PE Pulmonary embolism, Q1 First quartile, Q3 Third quartile, tPA tissue plasminogen activator
On the day of PE diagnosis, most patients required either no oxygen or oxygen provided by simple devices. Non-invasive ventilation was used in 8 patients (1.8%) and invasive ventilation in 7 (1.6%). The fraction of inspired oxygen was slightly higher in patients with central PE.
Systemic anticoagulation was provided for all except 4 patients (subsegmental PE [n = 1], multiple segmental PE [n = 2] and multiple lobar PE [n = 1]). Systemic thrombolysis was used in 19 patients (4.3%) and advanced endovascular therapy in 17 patients (3.9%). Patients with central PE had more systemic thrombolysis (13/133 [9.8%] versus 6/305 [2.0%], p < 0.0001) and more advanced endovascular therapy (15/133 [11.3%] versus 2/305 [0.7%], p < 0.0001). The two patients with peripheral PE had bilateral lobar PE with severe right ventricular strain. Inferior vena cava filters were inserted in 29 patients (6.6%) and more commonly in patients with central PE.
Outcomes
The outcomes of patients are described in Table 4. All-cause hospital mortality rate was 6.2% for the study cohort with no difference between central and peripheral PE (5.3% and 6.6%, respectively; p = 0.61). PE-related hospital mortality was 3.7% (4.5% for central PE and 3.3% for peripheral PE, p = 0.58). Six-month mortality could be assessed in 379 patients out of the 438 study patients and was 18.2% (16.4% for central PE and 19.0% for peripheral PE, p = 0.55).
Table 4.
Outcomes of patients
| Variables |
All patients N = 438 |
Peripheral PE N = 305 |
Central PE N = 133 |
P value |
|---|---|---|---|---|
| All-cause hospital mortality, N (%) | 27 (6.2) | 20 (6.6) | 7 (5.3) | 0.61 |
| Pulmonary embolism-related hospital mortality, N (%) | 16 (3.7) | 10 (3.3) | 6 (4.5) | 0.58 |
| Six-moth mortality, N (%) | 69/379 (18.2) | 51/269 (19.0) | 18/110 (16.4) | 0.55 |
| Unable to assess six-month mortality due to follow-up loss (% of study patients) | 59/438 (13.5) | 36/305 (11.8) | 23/133 (17.3) | 0.13 |
| Bleeding in a critical area or organ, N (%) | 27 (6.2) | 19 (6.2) | 8 (6.0) | 0.93 |
| Intracranial bleeding, N (%) | 7 (1.6) | 5 (1.6) | 2 (1.5) | 0.92 |
| Bleeding leading to blood transfusion, N (%) | 19 (4.3) | 13 (4.3) | 6 (4.5) | 0.91 |
| Fatal bleeding, N (%) | 8 (1.8) | 5 (1.6) | 3 (2.3) | 0.66 |
| ICU LOS (days) for patients who needed ICU admission, median (Q1, Q3) | 4.0 (2.0, 10.5) | 3.0 (7.0, 12.0) | 3.0 (2.0, 6.5) | 0.01** |
| Hospital LOS (days), median (Q1, Q3) | 6.0 (3.0, 11.0) | 5.0 (3.0, 11.0) | 7.0 (4.0, 11.0) | 0.03** |
ICU Intensive care unit, LOS Length of stay, MV Mechanical ventilation, Q1 First quartile, Q3 Third quartile, RRT Renal replacement therapy, VTE Venous thromboembolism
*Student t test
** Mann–Whitney U test
All-cause hospital mortality and six-month mortality rates according to the clot burden score are shown in Fig. 1. All-cause hospital mortality ranged between 0% and 11.1% (p = 0.66 for between-group differences). Six-month mortality ranged between 10.5% and 28.0% (p = 0.65 for between-group differences). Death in the hospital occurred in 2/102 patients (2.0%) with low-risk PE, 7/121 patients (5.8%) with intermediate-low risk PE, 7/70 patients (10.0%) with intermediate-high risk PE and 8/62 patients (12.9%) with high-risk PE (p = 0.03 for between-group differences). Figure 2 also shows all-cause hospital mortality rates in patient subgroups. In patients with intermediate-high risk PE, central PE was not associated with higher hospital mortality (6.4% versus 17.4%, p = 0.15). Among the 70 patients with subsegmental PE (single or multiple), all-cause hospital mortality was 8.6% (5.5% for patients with more proximal PE, p = 0.41) and six-month mortality was 11.3% (19.2% for patients with more proximal PE, p = 0.14). None of the 23 patients with saddle PE died in the hospital. Thrombus location was not associated with mortality in older patients, those with obesity and those who received systemic thrombolysis (Fig. 2).
Fig. 2.
All-cause hospital mortality in selected subgroups of patients with acute pulmonary embolism
Bleeding in a critical area or organ occurred in 27 patients (6.2%) with no difference in patients with peripheral and central PE. Intracranial hemorrhage occurred in 7 patients (1.6%); including one patient who had received systemic thrombolysis, and another who had received an endovascular procedure.
Predictors of mortality
The results of the multivariable logistic regression analyses are presented in Table 5. Central versus peripheral PE was not associated with all-cause hospital mortality (in model 1, odds ratio 0.392, 95% confidence interval 0.128, 1.199; in model 2, odds ratio 0.653, 95% confidence interval 0.242, 1.762). The variables associated with increased mortality risk were PESI (in model 1, odds ratio per one point increment 1.480, 95% confidence interval 0.977, 2.242) and intermediate-high or high vs. low or intermediate-low risk PE (in model 1, odds ratio 2.800, 95% confidence interval 0.999, 7.849).
Table 5.
Results of the multivariable logistic regression analysis for the predictors of hospital mortality and six-month mortality
| Hospital mortality | Six-month mortality | |||||||
|---|---|---|---|---|---|---|---|---|
| Model 1* | Model 2** | Model 1* | Model 2** | |||||
| Odds ratio (95% CI) | P-value | Odds ratio (95% CI) | P-value | Odds ratio (95% CI) | P-value | Odds ratio (95% CI) | P-value | |
| Age per year increment | 1.005 (0.976, 1.035) | 0.73 | 1.005 (0.977, 1.034) | 0.73 | 1.021 (1.000, 1.042) | 0.046 | 1.020 (1.000, 1.041) | 0.051 |
| Female vs. male sex | 1.584 (0.528, 4.756) | 0.41 | 1.611 (0.538, 4.827) | 0.39 | 0.900 (0.446, 1.816) | 0.77 | 0.931 (0.460, 1.881) | 0.84 |
| Obesity (BMI ≥ 30 kg/m2) vs. no obesity | 1.648 (0.643, 4.225) | 0.30 | 1.586 (0.624, 4.031) | 0.33 | 0.476 (0.235, 0.964) | 0.04 | 0.443 (0.219, 0.895) | 0.02 |
| Diabetes vs. no diabetes | 1.584 (0.528, 4.756) | 0.45 | 1.363 (0.455, 4.080) | 0.58 | 1.867 (0.844, 4.131) | 0.12 | 1.828 (0.831, 4.020) | 0.13 |
| Hypertension vs. no hypertension | 0.806 (0.246, 2.638) | 0.72 | 0.919 (0.288, 2.929) | 0.89 | 1.114 (0.469, 2.647) | 0.81 | 1.151 (0.488, 2.712) | 0.75 |
| Hyperlipidemia vs. no hyperlipidemia | 0.811 (0.283, 2.325) | 0.70 | 0.797 (0.279, 2.272) | 0.67 | 0.786 (0.386, 1.601) | 0.51 | 0.765 (0.377, 1.552) | 0.46 |
| History of myocardial infarction vs. no history | 0.609 (0.115, 3.221) | 0.56 | 0.646 (0.124, 3.355) | 0.60 | 0.383 (0.112, 1.312) | 0.13 | 0.418 (0.122, 1.435) | 0.17 |
| CKD vs. no CKD | 1.013 (0.252, 4.068) | 0.99 | 1.145 (0.293, 4.478) | 0.85 | 1.563 (0.595, 4.102) | 0.37 | 1.893 (0.720, 4.981) | 0.20 |
| Heart failure vs. no heart failure | 0.609 (0.115, 3.221) | 0.49 | 1.722 (0.402, 7.380) | 0.46 | 1.474 (0.530, 4.099) | 0.46 | 1.614 (0.579, 4.499) | 0.36 |
| COPD vs. no COPD | 0.609 (0.115, 3.221) | 0.89 | 0.964 (0.071, 13.130) | 0.98 | 0.979 (0.114, 8.420) | 0.99 | 0.843 (0.100, 7.096) | 0.88 |
| Malignancy vs. no malignancy | 1.336 (0.362, 4.930) | 0.66 | 1.340 (0.366, 4.903) | 0.66 | 1.893 (0.765, 4.679) | 0.17 | 2.018 (0.819, 4.976) | 0.13 |
| Previous VTE vs. no previous VTE | 0.000(0.000, -) | 1.0 | 0.000(0.000, -) | 1.0 | 0.393 (0.123, 1.256) | 0.12 | 0.348 (0.109, 1.109) | 0.07 |
| PE diagnosis after 48 h vs. within 48 h of admission | 1.336 (0.362, 4.930) | 0.41 | 0.636 (0.190, 2.127) | 0.46 | 1.012 (0.465, 2.201) | 0.98 | 1.011 (0.465, 2.196) | 0.98 |
| PESI per one point increment | 1.480 (0.977, 2.242) | 0.06 | 1.480 (0.985, 2.224) | 0.06 | 1.325 (0.985, 1.784) | 0.06 | 1.337 (0.996, 1.795) | 0.053 |
| Intermediate-high or high vs. low or intermediate low risk PE | 2.800 (0.999, 7.849) | 0.05 | 2.448 (0.872, 6.872) | 0.09 | 0.627 (0.284, 1.387) | 0.25 | 1.248 (0.595, 2.617) | 0.56 |
| Central vs. peripheral thrombus location | 0.392 (0.128, 1.199) | 0.10 | 0.653 (0.242, 1.762) | 0.40 | 1.598 (0.748, 3.413) | 0.23 | 1.391 (0.695, 2.783) | 0.35 |
*In model 1, central PE was defined as saddle PE or PE with thrombus in the main pulmonary artery and peripheral PE as PE with more distal thrombus
**In model 2, central PE was defined as saddle PE or PE with thrombus in the main pulmonary artery or a lobar artery and peripheral PE as PE with more distal thrombus
BMI Body mass index, CI Confidence interval, CKD Chronic kidney disease, COPD Chronic obstructive pulmonary disease, PE Pulmonary embolism, PESI Pulmonary embolism severity index, VTE Venous thromboembolism
Additionally, central versus peripheral PE was not associated with six-month mortality (in model 1, odds ratio 1.598, 95% confidence interval 0.748, 3.413; in model 2, odds ratio 1.391, 95% confidence interval 0.695, 2.783). The variables associated with increased mortality risk were age (in model 1, odds ratio per year increment 1.021, 95% confidence interval 1.000, 1.042), obesity (in model 1, odds ratio 0.476, 95% confidence interval 0.235, 0.964) and PESI (in model 1, odds ratio per one-point increment 1.325, 95% confidence interval 0.985, 1.784).
Discussion
In the current study, we found that central PE was less common than peripheral PE and was associated with more prevalent high-risk features such as elevated troponin I and right ventricular strain. Patients with peripheral PE were less likely to receive proper risk stratification. We also found that central and peripheral PE, including those in the subsegmental location, had similar all-cause hospital mortality.
Acute PE remains a common disease with significant mortality. The incidence of PE in the general population is approximately 60 to 120 cases per 100 000 population per year, with an in-hospital mortality of 14% and a 90-day mortality of 20% [19–21]. Variables that predict adverse outcomes include hemodynamic instability and cardiac injury [22]. Patients with high-risk/massive PE (hemodynamic instability) have the highest mortality risk (approximately 20% risk of 30-day mortality, compared with 5% for all other patients with PE) [2, 22]. In one study of patients with simplified PESI ≥ 1, the mortality was 2.5% in those with normal BNP and normal echocardiography (low-risk PE), 5.8% and 5.6% in patients with either elevated BNP or right ventricular strain on echocardiography (submassive/ intermediate-low risk PE), respectively and 10.8% in those with both elevated BNP and right ventricular strain (intermediate-high risk PE) [16]. In the current study, we observed a similar pattern of mortality; lowest in the low-risk PE group (2.0%) and highest in the high-risk risk group (12.9%).
Thrombus location in acute PE has received attention recently and is considered by many as a factor for prognostication and management decisions. However, the association of thrombus location with signs of cardiac injury is inconsistent. One study of 530 consecutive patients with PE found that central PE was associated with higher troponin I [8]. Another study found no association between PE location and troponin I [23]. The right ventricle-to-left ventricle dimensions assessed by multi-detector CTPA were different between central and peripheral PE only when using ECG-synchronized images [24]. We found that patients with central PE had higher levels of cardiac injury markers and higher prevalence of right ventricular strain by echocardiography (72.1%). Nevertheless, a significant proportion of patients with peripheral PE had cardiac injury and right ventricular strain (33.3%). We also found that in patients without hypotension, central thrombus location had 67% sensitivity, 80% specificity, 51% positive predictive value and 89% negative predictive value to correctly classify PE as intermediate-high risk. This diagnostic performance suggests that thrombus location has a limited value in PE risk assessment. We found that patients with peripheral PE were less likely to receive proper risk stratification, suggesting that physicians believed that peripheral PE had a better prognosis.
Studies on the association of central thrombus location with mortality showed conflicting results. One meta-analysis that included 5 studies (2215 patients) found that central thrombus location was associated with higher 30‐day mortality risk (odds ratio 2.24, 95% confidence interval 1.29, 3.89, I2 = 0%) [25]. However, in another meta-analysis, central thrombus location was not associated with all-cause mortality (odds ratio 1.7, 95% confidence interval 0.7, 4.2) [26]. We found that central and peripheral thrombus locations were associated with similar hospital mortality in patients with acute PE. Our study results might be explained by differences in baseline characteristics (i.e., patients with peripheral PE had higher prevalence of chronic kidney disease), less proper risk assessment and differences in PE management. Unmeasured confounding variables could also account for our findings. Nevertheless, thrombus location within the pulmonary arterial tree does not always correlate with PE severity. Mechanical obstruction alone cannot explain the increased right ventricular afterload and consequent right ventricular strain in PE [27]. Right ventricular strain may result from a complex interaction between humoral factors from the activated platelets, endothelial effects, reflexes and hypoxia that cause pulmonary vasoconstriction and increased right ventricular afterload [27]. We also found that simplified PESI and PE risk class (high and intermediate-high risk versus lower risk) were associated with mortality, which is consistent with other studies [2, 3, 16, 28]. While the absence of central PE makes the presence of an intermediate-high risk PE unlikely (negative predictive value of 89% in our study), our findings support that proper PE risk assessment should be primarily based on the patient’s characteristics, hemodynamic profile and markers of right ventricular strain rather than on thrombus location [3].
In the current study, 70 patients (16.0% of the study patients) had subsegmental PE. Subsegmental peripheral PE has been diagnosed more frequently after the use of multi-row detector CTPA. It is frequently thought to have a benign disease course and to be clinically irrelevant, [29] which makes its treatment a controversial issue. A systematic review and meta-analysis of observational studies and randomized controlled trials showed no significant difference in venous thromboembolism recurrence at 90 days between patients with subsegmental PE who were treated with anticoagulation and those not treated (5.3% versus 3.9%, respectively) and all-cause mortality (2.1% versus 3.0%, respectively) [30]. However, another systematic review of randomized controlled trials of anticoagulation therapy versus control found no high-quality data to support treating it differently from segmental or lobar PE [31]. Additionally, a recent observational study found that patients with subsegmental PE and no proximal deep-vein thrombosis who did not receive anticoagulation (N = 292) had a higher than expected rate of recurrent venous thromboembolism at 90 days, especially for patients with multiple subsegmental PE (recurrence rate was 5.7%) [32]. Another observational study found that 12 out of 116 patients (10.3%) with subsegmental PE died at 3 months compared with 40 out of 632 patients (6.3%) with more proximal PE [33]. Similar mortality was also seen in elderly patients [34]. We found that all-cause hospital mortality rate of patients with subsegmental PE was 8.6%, which was similar to that of patients with more proximal PE (5.5%, p = 0.41). The six-month mortality was 11.3% compared with 19.2% for those with more proximal PE (p = 0.14). Whether the mortality is related to PE, or the acute illness is unclear. Nevertheless, these data suggest that subsegmental PE may not have a better prognosis than more proximal PE and may warrant similar treatment approach. The current guidelines recommend screening for deep-vein thrombosis in patients with single subsegmental PE and favor anticoagulation in selected patients, including those who are symptomatic, hospitalized, or have persistent risk factors for venous thromboembolism [35].
The study should be interpreted taking into consideration the following limitations. The study was retrospective at a single center, which introduces selection bias and limits the generalizability of our findings. We excluded patients with COVID-19 as these patients may have different prognosis than non-COVID-19 patients. We also did not assess the volume of thrombi and the degree of arterial occlusion. Thrombus load and volume have been assessed on CTPA using different methods, with variable findings on their ability to predict outcomes [26, 36, 37]. Many patients with peripheral PE did not have troponin I or BNP. This suggests that the treating medical team assessed these patients as having low-risk PE. Incomplete data as well as unmeasured confounders may have affected our findings.
Conclusions
Although patients with central PE had higher rates of features of higher-risk PE, such as elevated cardiac injury markers and right ventricular strain, a significant proportion of those with peripheral PE had intermediate-high and high-risk PE. Our findings indicate that patients with central and peripheral PE, including subsegmental thrombus location, had similar all-cause and six-month mortality rates. These findings are not consistent with those of other studies and warrant further validation. Proper risk stratification, as per current guidelines, is essential for determining subsequent management for patients with central and peripheral PE.
Acknowledgements
None.
Institutional review board statement
This study (Study number NRC23R/809/12) was approved by the Institutional Review Board of National Guard – Health Affairs, Riyadh, Saudi Arabia. (IRB approval number: IRB/1720/23; Date December 31, 2023).
Informed consent statement
Informed consent was waived by the Institutional Review Board as the study used only electronic medical record review for data collection.
Authors' contributions
HMD: contributed to the study concept and design, contributed to data collection and interpretation, and performed statistical analysis. FMA, BAA, AOA, AMA, AMB, MMH, and YA contributed to data collection and interpretation. All authors drafted the manuscript, critically revised the manuscript, agree to be fully accountable for ensuring the integrity and accuracy of the work and read and approved the final manuscript. MK, AA and YA contributed to the study concept and data interpretation. All authors drafted the manuscript, critically revised the manuscript, agree to be fully accountable for ensuring the integrity and accuracy of the work and read and approved the final manuscript.
Funding
This research received no external funding.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
No datasets were generated or analysed during the current study.