Abstract
Background
Optimal dosing of alteplase for systemic thrombolysis in intermediate-risk pulmonary embolism (PE) remains controversial due to hemorrhagic risk. This retrospective cohort study analyzed data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database to evaluate dose-dependent efficacy and safety of alteplase in PE patients.
Methods
Patients with PE treated with systemic alteplase thrombolysis were stratified into two groups based on a clinically established dose threshold of 50 mg. The primary outcomes included 7-day mortality and changes in hemodynamic and respiratory parameters before and after alteplase administration. Secondary outcomes included the relationship between dose stratification and mortality at the intensive care unit (ICU), hospital, 28-, 60-, and 365-day, using Kaplan-Meier survival curves and Cox proportional hazards regression. Propensity score matching (PSM) was employed to minimize bias.
Results
After PSM, 122 patients were included, with 76 in the low-dose group and 46 in the high-dose group. Both groups showed improvements in heart rate (HR). In the high-dose group, partial thromboplastin time (PTT) and blood urea nitrogen (BUN) were significantly higher than in the low-dose group. The low-dose group had lower 7-day and ICU mortality rates than the high-dose group. Cox regression analysis showed that dose stratification was an independent risk factor for 7-day mortality [hazard ratio (HR): 0.289, 95% confidence interval (CI): 0.072–1.023, P=0.045].
Conclusions
This study suggests that low-dose alteplase (≤50 mg) is associated with a better balance between thrombolytic efficacy and safety.
Keywords: Pulmonary embolism (PE), alteplase, thrombolysis, Medical Information Mart for Intensive Care IV (MIMIC-IV)
Highlight box.
Key findings
• This study suggests that low-dose alteplase (≤50 mg) is associated with a better balance between thrombolytic efficacy and safety.
What is known and what is new?
• The optimal dosage of alteplase remains controversial due to limited evidence, despite its widespread use. A retrospective study was performed to compare the efficacy and safety of 50 vs. 100 mg alteplase in acute pulmonary embolism management. The results demonstrated that the 50 mg group exhibited a lower incidence of hemorrhagic complications, with most complications being minor in severity. Another study found no significant differences in mortality or bleeding rates between the 50 and 100 mg alteplase dosage groups.
• This retrospective study stratified pulmonary embolism (PE) patients receiving systemic thrombolysis from the Medical Information Mart for Intensive Care IV database into low-dose (≤50 mg) and high-dose (>50 mg) groups to evaluate efficacy and safety outcomes.
What is the implication, and what should change now?
• This study, through evaluating the dose-dependent efficacy and safety of alteplase in patients with PE, aims to assist clinicians in optimizing treatment regimens to reduce mortality and improve patient prognosis. To enhance the robustness and generalizability of the findings, future research should focus on increasing sample size, optimizing data collection methods, and designing additional prospective studies.
Introduction
Pulmonary embolism (PE) persists as a leading contributor to global cardiovascular morbidity and mortality. In Germany, epidemiological data indicate an incidence rate of 109 cases per 100,000 population (1), with a hospital mortality rate reaching 13.9%. Among critically ill patients requiring intensive care unit (ICU) admission, the incidence of PE or lower extremity deep vein thrombosis is 2.2% (2,3). Although overall mortality rates have shown a declining trend, the age-standardized mortality rate for PE in Europe remains significant at 6.5 per 100,000 population (4). The annual incidence of acute pulmonary embolism (APE) is reported to be 83 cases per 100,000 population, with mortality rates of 11% at 30 days and 18% at 90 days post-diagnosis (5). PE is the third most common cause of cardiovascular death after myocardial infarction and stroke (6,7).
As a result, systemic thrombolysis has gained wider acceptance in clinical practice for the management of PE (1,7). The simplified Pulmonary Embolism Severity Index (sPESI) has become a widely implemented prognostic tool for risk stratification in PE patients (8,9). This scoring system categorizes patients into low-risk (0 point) and intermediate-risk (≥1 point) groups (10,11). The European Society of Cardiology has further refined this classification into four categories: high-risk, intermediate-high-risk, intermediate-low-risk, and low-risk. Current guidelines recommend thrombolytic therapy as the primary intervention for high-risk patients, as it facilitates rapid restoration of pulmonary perfusion, reduces hospitalization duration, and improves survival outcomes. However, the therapeutic benefits of thrombolysis in intermediate-risk patient populations remain a topic of ongoing debate (12,13).
Alteplase, a recombinant tissue plasminogen activator, is commonly used for its ability to enhance coagulation parameters and improve right ventricular function in PE (14-16). The optimal therapeutic window for thrombolysis is within 48 hours of symptom onset. However, current guidelines indicate that thrombolytic therapy may still be effective for patients with symptoms lasting from 6 to 14 days (12). Despite its widespread use, the optimal dosage of alteplase remains controversial due to limited evidence. A retrospective study comparing the efficacy and safety of 50 vs. 100 mg alteplase in APE management found significant improvements in shock index, blood pressure, heart rate (HR), respiratory rate (RR), and oxygen requirements for both doses. However, the 50 mg group exhibited a lower incidence of hemorrhagic complications, with most complications being minor in severity (17). Another study found no significant differences in mortality or bleeding rates between the 50 and 100 mg alteplase dosage groups. However, the 50 mg alteplase dosage group was associated with increased treatment escalation (18). Prospective studies have explored alternative dosing regimens. One study demonstrated the safety and efficacy of an extended infusion of 25 mg alteplase in high-risk PE patients (19), while another study highlighted the benefits of systemic thrombolysis with 20 mg alteplase (20). Given the variability in patient characteristics, including clinical condition, weight, age, and comorbidities, the selection of an appropriate alteplase dosage for systemic thrombolysis remains a topic of debate. Therefore, in this retrospective cohort study, we stratified patients with PE receiving systemic thrombolytic therapy into a low-dose group (≤50 mg) and a high-dose group (>50 mg), using the clinically established 50 mg alteplase threshold to evaluate the efficacy and safety of different dosing regimens and inform evidence-based thrombolytic strategies in clinical practice. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2390/rc).
Methods
Data source
This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (v2.2), a publicly available repository curated by the Massachusetts Institute of Technology. The database encompasses 431,233 hospitalization records and 73,181 ICU admissions from 299,712 patients treated at Beth Israel Deaconess Medical Center (Boston, MA, USA) between 2008 and 2019. All protected health information was de-identified, and patient identifiers were replaced with randomized codes. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was exempted from ethical approval and informed consent requirements. The authors obtained permission to use the database (Certificate Numbers: 61274028, 61274029).
Study population
Patients with PE were initially identified using International Classification of Diseases, Ninth and Tenth Revision (ICD-9/10) codes (Table S1), yielding an initial cohort of 2,759 cases. The inclusion criteria were as follows: (I) patients with PE; (II) first-time ICU admission; and (III) age ≥18 years. Exclusion criteria included: (I) patients who did not receive alteplase thrombolysis (n=2,250); (II) those undergoing catheter-directed thrombolysis (n=369). The final analysis included 140 patients diagnosed with PE who underwent systemic alteplase thrombolytic therapy (Figure 1).
Figure 1.
Flow chart of the study participants PE. ICU, intensive care unit; MIMIC-IV, Medical Information Mart for Intensive Care IV; PE, pulmonary embolism.
Data extraction
Navicat Premium software (v.16, PremiumSoft) was used for data extraction through Structured Query Language. The sPESI was calculated from extracted comorbidity data. The information included: (I) intervention: total dose of alteplase; (II) baseline characteristics: age, gender, race, and weight; (III) comorbidities: congestive heart failure, malignant cancer, kidney disease, chronic obstructive pulmonary disease (COPD), hypertension, obesity, diabetes, and surgical history (cardiovascular surgery, lung surgery, thoracic surgery, abdominal surgery, esophageal surgery, colon surgery, hip replacement, knee replacement); (IV) the earliest vital signs before and after thrombolysis: HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), RR, partial pressure of oxygen (PO2), and oxygen saturation (SPO2); (V) the earliest laboratory parameters before and after thrombolysis: prothrombin time (PT), partial thromboplastin time (PTT), blood urea nitrogen (BUN), and mean corpuscular hemoglobin concentration (MCHC); (VI) disease severity scores: Simplified Acute Physiology Score II (SAPSII), sPESI; (VII) complications: acute kidney injury (AKI), pulmonary hypertension, and temperature; (VIII) clinical treatments: mechanical ventilation, heparin therapy.
Outcome measures
The primary outcomes included 7-day all-cause mortality and changes in hemodynamic and respiratory parameters before and after alteplase administration. Secondary outcomes included 28-, 60-, and 365-day mortality, hospital mortality, ICU mortality, and ICU and hospital length of stay (LOS). Because the MIMIC IV database is linked to the social security database, all patients were followed for 365 days with no loss to follow-up.
Statistical analysis
Missing data were imputed using the Random Forest algorithm via the ‘mice’ package. Normality of continuous variables was assessed using the Shapiro-Wilk test. Normally distributed variables were expressed as mean ± standard deviation (SD) and compared with independent t-tests; non-normal variables were reported as median (interquartile range, IQR) and analyzed using Mann-Whitney U tests. Categorical variables were presented as frequencies (%) and compared with χ2 or Fisher’s exact tests. Longitudinal changes in secondary outcomes were evaluated using paired t-tests (normal distribution) or Wilcoxon signed-rank tests (non-normal distribution).
The association between dose stratification and mortality at ICU, hospital, 28-, 60-, and 365-day was assessed using Kaplan-Meier survival curves and Cox proportional hazards regression. PSM was applied to adjust for the imbalance in baseline characteristics between the two groups. Multicollinearity among covariates was assessed using variance inflation factors (VIFs) (Table S2), with variable correlations visualized in Figure S1. Statistical analyses were conducted using R version 4.4.1 and SPSS 26.0, with P<0.05 (two-sided) considered statistically significant.
Results
Baseline characteristics
Table 1 summarizes the baseline characteristics of patients with PE. A total of 140 patients were included in the retrospective analysis, with 89 patients in the low-dose group and 51 patients in the high-dose group. Among these, 99 patients (70.7%) were classified as intermediate risk, while 41 patients (29.3%) were classified as low-risk based on the sPESI risk score. Notably, no Black patients were present in the high-dose group [13 of 89 (14.6%) vs. 0 of 51 (0%), P=0.003]. No significant differences were observed between the groups in terms of age, gender, comorbidities, or laboratory values (Table 1 and Table S3).
Table 1. Baseline characteristics of patients with PE undergoing systemic thrombolysis.
| Variable | Before PSM | After PSM | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Total (n=140) | Low-dose (n=89) | High-dose (n=51) | P | Total (n=122) | Low-dose (n=76) | High-dose (n=46) | P | ||
| Age (years) | 59.0±15.8 | 58.4±15.7 | 60.1±16.0 | 0.55 | 59.6±15.9 | 59.8±15.7 | 59.3±16.5 | 0.86 | |
| Gender | |||||||||
| Male | 76 (54.3) | 51 (57.3) | 25 (49.0) | 0.38 | 68 (55.7) | 46 (60.5) | 22 (47.8) | 0.19 | |
| Female | 64 (45.7) | 38 (42.7) | 26 (51.0) | 0.38 | 54 (44.3) | 30 (39.5) | 24 (52.2) | 0.19 | |
| Weight (kg) | 90.0 (75.7–114.0) | 88.9 (77.0–112.4) | 93.8 (73.1–115.0) | 0.47 | 90.5 (77.1–114.0) | 89.7 (77.4–112.8) | 97.6 (75.4–115.5) | 0.37 | |
| Race | |||||||||
| White | 93 (66.4) | 59 (66.3) | 34 (66.7) | 0.003 | 89 (73.0) | 59 (77.6) | 30 (65.2) | 0.15 | |
| Black | 13 (9.3) | 13 (14.6) | 0 (0.0) | 0.003 | 0 (0.0) | 0 (0.0) | 0 (0.0) | – | |
| Other | 34 (24.3) | 17 (19.1) | 17 (33.3) | 0.003 | 33 (27.0) | 17 (22.4) | 16 (34.8) | 0.15 | |
| Comorbidities (yes) | |||||||||
| Obesity | 36 (25.7) | 22 (24.7) | 14 (27.5) | 0.84 | 31 (25.4) | 18 (23.7) | 13 (28.3) | 0.68 | |
| COPD | 37 (26.4) | 25 (28.1) | 12 (23.5) | 0.70 | 36 (29.5) | 24 (31.6) | 12 (26.1) | 0.55 | |
| Congestive heart failure | 31 (22.1) | 21 (23.6) | 10 (19.6) | 0.68 | 28 (23.0) | 18 (23.7) | 10 (21.7) | 0.83 | |
| Diabetes | 36 (25.7) | 22 (24.7) | 14 (27.5) | 0.84 | 29 (23.8) | 17 (22.4) | 12 (26.1) | 0.66 | |
| Hypertension | 75 (53.6) | 45 (50.6) | 30 (58.8) | 0.38 | 64 (52.5) | 38 (50.0) | 26 (56.5) | 0.58 | |
| Renal disease | 12 (8.6) | 5 (5.6) | 7 (13.7) | 0.12 | 4 (3.3) | 2 (2.6) | 2 (4.3) | 0.63 | |
| Malignant cancer | 24 (17.1) | 17 (19.1) | 7 (13.7) | 0.48 | 20 (16.4) | 15 (19.7) | 5 (10.9) | 0.22 | |
| Surgery | 74 (52.9) | 52 (58.4) | 22 (43.1) | 0.12 | 65 (53.3) | 44 (57.9) | 21 (45.7) | 0.20 | |
| Severity score | |||||||||
| sPESI (low-risk) | 41 (29.3) | 28 (31.5) | 13 (25.5) | 0.56 | 35 (28.7) | 22 (28.9) | 13 (28.3) | >0.99 | |
| SAPS II | 27.0 (19.0–41.2) | 27.0 (19.0–38.0) | 28.0 (19.5–51.0) | 0.14 | 28.0 (20.0–40.0) | 29.0 (20.8–38.0) | 26.5 (18.2–48.8) | 0.93 | |
Data are presented as mean ± standard deviation, n (%) or median (interquartile range). COPD, chronic obstructive pulmonary disease; PE, pulmonary embolism; PSM, propensity score matching; SAPS II, Simplified Acute Physiology Score II; sPESI, simplified Pulmonary Embolism Severity Index.
After PSM, 76 patients from the low-dose group were matched with 46 patients in the high-dose group, and no significant differences were found in baseline characteristics between the two groups. The mean age of the patients was 59.6±15.9 years, with a weight of 90.5 (77.1–114.0) kg. Sixty-eight patients (55.7%) were male, and 89 patients (73.0%) were White.
Clinical outcomes
Table 2 presents the laboratory values before and after thrombolysis. After PSM, the high-dose group showed a significant change in PT after thrombolysis (P=0.04) and PO2 (P=0.01). Compared to the low-dose group, the high-dose group had higher PTT [66.0 (35.2–88.3) vs. 50.8 (31.4–70.3) s, P=0.02] and higher BUN after thrombolysis [19.0 (11.0–31.0) vs. 14.0 (10.0–22.0) mg/dL, P=0.04]. Both dosage groups exhibited improvements in HR (P=0.02 in high-dose vs. P=0.03 in low-dose).
Table 2. Outcomes of patients with PE undergoing systemic thrombolysis (after PSM).
| Laboratory indicators | Total (n=122) | Low-dose (n=76) | High-dose (n=46) | P |
|---|---|---|---|---|
| PT (s) | ||||
| Before | 13.6 (12.4–15.8) | 13.8 (12.6–15.6) | 13.4 (12.4–17.3) | >0.99 |
| After | 13.9 (12.9–16.5) | 13.8 (13.0–16.2) | 14.0 (12.7–16.6) | 0.79 |
| P (before vs. after) | – | 0.15 | 0.04 | |
| PTT (s) | ||||
| Before | 57.2 (34.1–94.2) | 53.0 (33.0–79.0) | 62.3 (34.8–131.4) | 0.14 |
| After | 54.0 (31.8–76.8) | 50.8 (31.4–70.3) | 66.0 (35.2–88.3) | 0.02 |
| P (before vs. after) | – | 0.26 | 0.14 | |
| PO2 (mmHg) | ||||
| Before | 54.0 (42.2–78.8) | 54.0 (42.8–83.0) | 53.5 (42.5–77.8) | 0.91 |
| After | 74.0 (42.0–114.0) | 66.0 (42.0–101.0) | 78.0 (47.5–119.5) | 0.17 |
| P (before vs. after) | – | 0.11 | 0.01 | |
| MCHC (g/dL) | ||||
| Before | 32.4±1.7 | 32.4±1.6 | 32.4±1.9 | 0.88 |
| After | 32.4± 1.7 | 32.3±1.6 | 32.7±1.8 | 0.17 |
| P (before vs. after) | – | 0.053 | 0.051 | |
| BUN (mg/dL) | ||||
| Before | 15.5 (12.0–21.8) | 15.0 (12.0–20.0) | 16.0 (13.0–26.0) | 0.42 |
| After | 14.5 (10.2–24.0) | 14.0 (10.0–22.0) | 19.0 (11.0–31.0) | 0.04 |
| P (before vs. after) | – | 0.45 | 0.22 | |
| HR (beats/min) | ||||
| Before | 94.2±21.5 | 93.1±19.4 | 96.1±24.7 | 0.48 |
| After | 88.3±20.6 | 87.5±19.1 | 89.6±23.1 | 0.61 |
| P (before vs. after) | – | 0.03 | 0.02 | |
| SBP (mmHg) | ||||
| Before | 118.9±23.4 | 120.9±23.1 | 115.4±23.6 | 0.21 |
| After | 116.0 (108.0–130.0) | 118.0 (108.0–130.2) | 115.5 (107.5–127.2) | 0.46 |
| P (before vs. after) | – | 0.45 | 0.67 | |
| DBP (mmHg) | ||||
| Before | 73.3±17.8 | 74.2±19.2 | 71.8±15.5 | 0.45 |
| After | 70.1±16.4 | 71.5±16.8 | 67.8±15.7 | 0.23 |
| P (before vs. after) | – | 0.27 | 0.21 | |
| RR (beats/min) | ||||
| Before | 21.0 (17.2–25.9) | 21.0 (17.0–25.1) | 20.8 (19.0–26.0) | 0.84 |
| After | 21.0 (18.0–26.0) | 22.0 (17.8–24.0) | 21.0 (19.0–29.0) | 0.32 |
| P (before vs. after) | – | 0.56 | 0.93 | |
| SPO2 (%) | ||||
| Before | 96.0 (94.0–98.0) | 96.0 (94.0–98.0) | 95.5 (94.0–97.0) | 0.51 |
| After | 97.0 (93.2–98.0) | 96.0 (93.0–98.0) | 96.5 (94.0–98.0) | 0.96 |
| P (before vs. after) | – | 0.74 | 0.83 |
Data are presented as median (interquartile range) or mean ± standard deviation. BUN, blood urea nitrogen; DBP, diastolic blood pressure; HR, heart rate; MCHC, mean corpuscular hemoglobin concentration; PE, pulmonary embolism; PO2, partial pressure of oxygen; PSM, propensity score matching; PT, prothrombin time; PTT, partial thromboplastin time; RR, respiratory rate; SBP, systolic blood pressure; SPO2, oxygen saturation.
After PSM, the 7-day mortality rate was significantly higher in the high-dose group compared to the low-dose group (15.2% vs. 3.9%, P=0.04). ICU mortality was also significantly higher in the high-dose group (23.9% vs. 7.9%, P=0.02). No significant differences were observed between the groups in hospital mortality, 28-, 60-, or 365-day mortality, nor in ICU and hospital LOS. Four patients in the low-dose group developed pulmonary hypertension after thrombolysis. Additionally, 61.5% of patients developed AKI, 27.0% of patients had an abnormal temperature (≥37.5 ℃), 80.3% of patients required mechanical ventilation, and 95.9% of patients needed combined heparin anticoagulation, with no significant between-group differences. The detailed results are presented in Table 3. This study suggests an association between low-dose alteplase and more favorable changes in hemodynamic and respiratory parameters compared with the high-dose group.
Table 3. Outcomes of patients with PE undergoing systemic thrombolysis.
| Variable | Before PSM | After PSM | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Total (n=140) | Low-dose (n=89) | High-dose (n=51) | P | Total (n=122) | Low-dose (n=76) | High-dose (n=46) | P | ||
| Clinical outcomes | |||||||||
| Hospital mortality | 28 (20.0) | 15 (16.9) | 13 (25.5) | 0.28 | 27 (21.3) | 14 (18.4) | 13 (28.3) | 0.25 | |
| ICU mortality | 17 (12.1) | 6 (6.7) | 11 (21.6) | 0.02 | 17 (13.9) | 6 (7.9) | 11 (23.9) | 0.02 | |
| 7-day mortality | 11 (7.9) | 4 (4.5) | 7 (13.7) | 0.10 | 10 (8.2) | 3 (3.9) | 7 (15.2) | 0.04 | |
| 28-day mortality | 29 (20.7) | 15 (16.9) | 14 (27.5) | 0.19 | 27 (22.1) | 14 (18.4) | 13 (28.3) | 0.27 | |
| 60-day mortality | 34 (24.3) | 19 (21.3) | 15 (29.4) | 0.32 | 31 (25.4) | 18 (23.7) | 13 (28.3) | 0.67 | |
| 365-day mortality | 47 (33.6) | 30 (33.7) | 17 (33.3) | >0.99 | 43 (35.2) | 28 (36.8) | 15 (32.6) | 0.69 | |
| LOS-hospital (days) | 7.9 (4.1–18.2) | 7.7 (4.0–17.5) | 9.8 (4.9–18.3) | 0.79 | 8.0 (4.3–18.2) | 8.0 (4.1–19.4) | 7.9 (4.9–17.7) | 0.77 | |
| LOS-ICU (days) | 2.2 (1.5–5.0) | 2.0 (1.2–4.0) | 2.5 (1.7–5.7) | 0.30 | 2.2 (1.3–5.0) | 2.0 (1.2–4.8) | 2.3 (1.7–5.5) | 0.55 | |
| Complications | |||||||||
| Temperature (≥37.5 ℃) | 40 (28.6) | 22 (24.7) | 18 (35.3) | 0.24 | 33 (27.0) | 17 (22.4) | 16 (34.8) | 0.14 | |
| Pulmonary hypertension | 6 (4.3) | 6 (6.7) | 0 (0.0) | 0.09 | 4 (3.28) | 4 (5.3) | 0 (0.0) | 0.30 | |
| AKI | 87 (62.1) | 53 (59.6) | 34 (66.7) | 0.47 | 75 (61.5) | 46 (60.5) | 29 (63.0) | 0.85 | |
| Clinical treatment | |||||||||
| Mechanical ventilation | 108 (77.1) | 68 (76.4) | 40 (78.4) | 0.84 | 98 (80.3) | 61 (80.3) | 37 (80.4) | >0.99 | |
| Heparin | 133 (95.0) | 85 (95.5) | 48 (94.1) | 0.71 | 117 (95.9) | 74 (97.4) | 43 (93.5) | 0.36 | |
Data are presented as n (%) or median (interquartile range). AKI, acute kidney injury; LOS-ICU, intensive care unit length of stay; PE, pulmonary embolism; PSM, propensity score matching.
Survival analysis
Kaplan-Meier survival analysis was performed to compare all-cause mortality during ICU stay, during hospitalization, and at 7-, 28-, 60-, and 365-day follow-up intervals between the low-dose and high-dose groups. Before PSM, the low-dose group showed the highest survival probability at 7 days (log-rank test: P=0.050) and in the ICU (log-rank test: P=0.047) compared to the high-dose group (Figure 2). No significant differences were observed in hospital (log-rank test: P=0.09), 28-day (log-rank test: P=0.13), 60-day (log-rank test: P=0.24), or 365-day mortality (log-rank test: P=0.83) (Figures 2,3). After PSM, the low-dose group showed a higher survival probability at 7 days and in the ICU compared to the high-dose group (log-rank test: 7-day mortality P=0.03; ICU mortality P=0.048) (Figure 2). However, no significant differences were observed in hospital mortality, 28-, 60-, or 365-day mortality rates (log-rank test: hospital mortality P=0.06; 28-day mortality P=0.18; 60-day mortality P=0.47; 365-day mortality P=0.86) (Figures 2,3).
Figure 2.
Kaplan-Meier survival analysis curves illustrating mortality in patients with PE at 7 days (A,B), ICU (C,D), and hospital (E,F) following hospital admission, comparing outcomes before (A,C,E) and after (B,D,F) propensity score matching. ICU, intensive care unit; PE, pulmonary embolism.
Figure 3.
Kaplan-Meier survival analysis curves illustrating mortality in patients with PE at 28 days (A,B), 60 days (C,D), and 365 days (E,F) following hospital admission, comparing outcomes before (A,C,E) and after (B,D,F) propensity score matching. PE, pulmonary embolism.
After PSM, multivariate Cox regression suggested that dose stratification was an independent risk factor for 7-day mortality, as shown in Table 4 [hazard ratio (HR): 0.289, 95% confidence interval (CI): 0.072–1.023, P=0.045]. Univariate analysis demonstrated associations between dose stratification and ICU mortality as well as hospital mortality (ICU HR: 0.356, 95% CI: 0.122–1.034, P=0.04; hospital HR: 0.463, 95% CI: 0.206–1.041, P=0.049), though these associations were attenuated in multivariate models (Tables S4,S5) (ICU HR: 0.359, 95% CI: 0.123–1.048, P=0.06; hospital HR: 1.070, 95% CI: 0.900–4.762, P=0.09).
Table 4. Univariate and multivariate analysis of 7-day mortality.
| Variable | Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | ||
| Low-dose group | 0.248 | 0.064–0.959 | 0.04 | 0.289 | 0.072–1.023 | 0.045 | |
| Gender (female) | 3.076 | 0.795–11.898 | 0.10 | ||||
| Race (other) | 0.523 | 0.148–1.854 | 0.32 | ||||
| Obesity (no) | 1.365 | 0.290–6.429 | 0.69 | ||||
| Hypertension (no) | 0.462 | 0.120–1.788 | 0.26 | ||||
| Diabetes (no) | 0.456 | 0.129–1.616 | 0.22 | ||||
| Renal disease (no) | 0.284 | 0.036–2.241 | 0.23 | ||||
| COPD (no) | 0.974 | 0.252–3.765 | 0.97 | ||||
| Congestive heart failure (no) | 1.216 | 0.258–5.728 | 0.80 | ||||
| Malignant cancer (no) | 1.848 | 0.234–14.584 | 0.56 | ||||
| Surgery (no) | 1.102 | 0.717–10.727 | 0.14 | ||||
| Age | 1.028 | 0.985–1.072 | 0.21 | ||||
| Weight | 1.003 | 1.001–1.005 | 0.008 | 1.002 | 1.001–1.006 | 0.06 | |
CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio.
Cox proportional hazards model results showed that in Model 1, a low-dose (≤50 mg) was associated with reduced risks of 7-day mortality, ICU mortality, and hospital mortality (7-day mortality HR: 0.248, 95% CI: 0.064–0.959, P=0.04; ICU mortality HR: 0.356, 95% CI: 0.122–1.034, P=0.04; hospital mortality HR: 0.463, 95% CI: 0.206–1.041, P=0.049). After adjusting for age and weight in Model 2, the association with 7-day mortality remained borderline statistically significant (HR: 0.280, 95% CI: 0.070–1.128, P=0.050). The detailed results are presented in Table 5.
Table 5. The association between dose group and mortality.
| Outcome | HR (95% CI) | |
|---|---|---|
| Model 1 | Model 2 | |
| 7-day mortality | ||
| Low-dose group | 0.248 (0.064–0.959) | 0.280 (0.070–1.128) |
| High-dose group | 1 | 1 |
| P | 0.04 | 0.050 |
| Hospital mortality | ||
| Low-dose group | 0.463 (0.206–1.041) | 0.512 (0.224–1.173) |
| High-dose group | 1 | 1 |
| P | 0.049 | 0.11 |
| ICU mortality | ||
| Low-dose group | 0.356 (0.122–1.034) | 0.432 (0.144–1.296) |
| High-dose group | 1 | 1 |
| P | 0.04 | 0.13 |
| 28-day mortality | ||
| Low-dose group | 0.602 (0.283–1.281) | 0.609 (0.281–1.320) |
| High-dose group | 1 | 1 |
| P | 0.19 | 0.21 |
| 60-day mortality | ||
| Low-dose group | 0.772 (0.378–1.575) | 0.806 (0.387–1.682) |
| High-dose group | 1 | 1 |
| P | 0.48 | 0.57 |
| 365-day mortality | ||
| Low-dose group | 1.056 (0.564–1.978) | 1.076 (0.566–2.045) |
| High-dose group | 1 | 1 |
| P | 0.86 | 0.82 |
Model 1: unadjusted. Model 2: adjusted for weight and age. CI, confidence interval; HR, hazard ratio; ICU, intensive care unit.
Discussion
The present study suggests that thrombolysis with alteplase is associated with improvements in both hemodynamic and respiratory parameters in patients with PE, particularly in intermediate-risk patients. Our findings also highlight the importance of dose selection in the efficacy and safety of alteplase treatment (21,22). Specifically, we observed that the low-dose group was associated with lower 7-day and ICU mortality compared to the high-dose group. This supports an association between a 50-mg dose and a potentially superior safety profile in the treatment of PE, which is consistent with prior research (23).
Lehnert et al. reported a decline in 30-day mortality among patients with PE from 17% in 2004 to 11% in 2014 (5), while Melamed et al. reported a 7-day mortality rate of 6.7% (17). In our cohort, the 7- and 28-day all-cause mortality rates were 7.9% and 20.7%, respectively—slightly higher than those in prior studies. Several factors may account for this discrepancy. First, a subset of patients received repeated thrombolytic therapy, a practice that may confer a higher mortality risk compared to single-dose administration (24). Second, our cohort had a substantial comorbidity burden; notably, 74 patients (52.9%) had concomitant surgical conditions, which have a connection to outcomes in PE (25-27). Finally, this study is based on the MIMIC-IV single-center retrospective database, which covers data from 2008 to 2019 and reflects the evolving clinical practices and treatment protocols over time, potentially contributing to variations in outcomes. Although PSM and Cox regression were used to adjust for known confounders, residual confounding (such as unmeasured thrombus burden) and selection bias (due to clinicians assigning doses based on individual risk) may still affect the results.
Our study found that only in the higher-dose alteplase treatment group was a statistically significant increase in PT values observed in patients after thrombolysis. Furthermore, post-thrombolysis levels of PTT and BUN were higher in the high-dose group compared with the low-dose group. These differences in laboratory parameters may reflect more pronounced disturbances in coagulation or renal function—alterations that have been associated with an increased risk of bleeding in prior studies (14,28,29). However, our analysis did not include systematically adjudicated clinical bleeding outcomes (e.g., major or life-threatening hemorrhage), so we cannot directly assess the impact of dose stratification on actual bleeding events (30). Therefore, these differences in laboratory parameters are considered as potential safety signals, and future prospective studies should further validate this result using standardized bleeding endpoints.
Cox regression analysis identified dose as the independent risk factor for 7-day mortality. Figure S1 demonstrated weak to moderate correlations (|r|<0.5) between most variables, suggesting that multicollinearity was not a significant issue. Furthermore, VIF values for all variables were below 5, indicating that multicollinearity was within acceptable limits (Table S2). The proportional hazards assumption was assessed using Schoenfeld residuals, which showed no significant violations, suggesting the validity of the Cox proportional hazards model used in this analysis (Figure S2 and Table S6). This finding may be influenced by limited statistical power due to the relatively small sample size. The low number of events related to comorbidities might have further limited the power of the analysis, suggesting that larger studies with more robust statistical power are required to definitively confirm the independent effects of dose escalation on mortality.
While this study primarily evaluates the effects of alteplase monotherapy, the emergence of third-generation thrombolytic agents such as tenecteplase and reteplase warrants further investigation (31). A Recent Study has suggested that tenecteplase may be associated with a higher incidence of bleeding compared to alteplase (32). At the same time, Reteplase has demonstrated favorable outcomes in ischemic stroke patients treated within 4.5 hours of symptom onset (33). These newer agents may provide an alternative approach to thrombolysis in PE and should be evaluated for their comparative efficacy and safety profiles in this context.
Another avenue for future research involves exploring the potential synergistic effects of combining anticoagulants with thrombolytic agents in the management of PE. The PEITHO-3 trial, for instance, assessed the use of low-dose intravenous alteplase in combination with heparin anticoagulation, demonstrating promising results (22). Similarly, a prospective study showed that a 25-mg alteplase regimen co-administered with heparin was safe and effective (19). These combination strategies might optimize patient outcomes, and future studies could focus on determining more effective thrombolysis-anticoagulation combinations.
This study suggested that low-dose alteplase well-balanced the demands of both safety and efficacy. However, considering clinical patients in specifically stressed states, such as postoperatively with coagulation disorders, the tolerance to thrombolytic doses may differ from that in the general population. Therefore, thrombolytic management strategies in these patient populations require more detailed optimization.
A strength of this study lies in the incorporation of multidimensional clinical parameters—including MCHC, BUN, and the sPESI—as covariates to assess mortality risk in patients with PE. This selection of covariates was informed by previous studies: Zhou et al. combined MCHC and sPESI to predict 30-day mortality in PE patients (34), while Morillo et al. incorporated additional factors, including deep vein thrombosis, plasma creatinine, and immobilization (35).
There are several limitations in this study. Firstly, the retrospective observational design may introduce potential confounding biases, making it impossible to fully exclude the impact of unmeasured variables on the results. Secondly, the sample size is relatively small, and the distribution of patients across dose groups is imbalanced. This imbalance, combined with the limited number of outcome events (particularly short-term mortality), may reduce statistical power, leading to unstable effect estimates [such as fluctuations in hazard ratios (HRs)] and widened confidence intervals. The insufficient sample size in the high-dose group further limits the ability to fully adjust for confounding factors. Even after employing PSM, residual confounding risks may still be present. To further validate the observed effects and enhance the reliability of the conclusions, future studies should consider using larger and more balanced sample sizes and employing more precise statistical methods to minimize potential confounding biases. Additionally, while relevant covariates were included based on the sPESI score and clinical experience, incomplete extraction of surgical data and comorbidities may have hindered a more thorough analysis of their impact on patient mortality. Future research should aim to more comprehensively extract these variables to better understand the role of surgical type and comorbid conditions in patient outcomes (36,37). Furthermore, the exclusion of a subset of Black patients during the PSM process, resulting in a predominantly composed of White patient population (73.0%, 89 patients), limits the generalizability of the findings (38,39). Given potential racial differences in coagulation parameters, future studies should investigate the impact of racial variability on thrombolytic dosing and strive for more diverse patient populations to enhance the robustness of the results.
Future studies could integrate additional data, such as imaging assessments of thrombus location and size, to better understand treatment effects (40). Echocardiography could also be used to evaluate right ventricular function before and after thrombolysis (41,42). Moreover, systematically recording alteplase infusion rates and time windows could provide valuable insights into the dose-dependent effects of systemic alteplase in PE treatment (19,42). Given the heterogeneity of the patient population and variability in comorbidities, further stratification and personalized treatment strategies should be explored to improve clinical outcomes. To enhance the robustness and generalizability of the findings, future research should focus on increasing sample size, optimizing data collection methods, and designing additional prospective studies.
Conclusions
This study suggests that low-dose alteplase (≤50 mg) for systemic thrombolysis correlates with lower 7-day mortality in patients with PE compared to high-dose alteplase (>50 mg). Additionally, the low-dose group presents more favorable improvements in hemodynamic and respiratory parameters after alteplase administration. These findings indicate that low-dose alteplase (≤50 mg) may offer a better balance between thrombolytic efficacy and bleeding risk.
Supplementary
The article’s supplementary files as
Acknowledgments
We greatly acknowledge the diligent efforts of the personnel responsible for the design and maintenance of the MIMIC IV database.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2390/rc
Funding: This work was supported by the Medical Scientific Research Project of Jiangsu Health Commission (grant No. ZD2021011) and the National Natural Science Foundation of China (grant Nos. 82002454 and 82273325).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2390/coif). The authors have no conflicts of interest to declare.
References
- 1.Keller K, Hobohm L, Ebner M, et al. Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany. Eur Heart J 2020;41:522-9. 10.1093/eurheartj/ehz236 [DOI] [PubMed] [Google Scholar]
- 2.Eck RJ, Hulshof L, Wiersema R, et al. Incidence, prognostic factors, and outcomes of venous thromboembolism in critically ill patients: data from two prospective cohort studies. Crit Care 2021;25:27. 10.1186/s13054-021-03457-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Millington SJ, Aissaoui N, Bowcock E, et al. High and intermediate risk pulmonary embolism in the ICU. Intensive Care Med 2024;50:195-208. 10.1007/s00134-023-07275-6 [DOI] [PubMed] [Google Scholar]
- 4.Barco S, Mahmoudpour SH, Valerio L, et al. Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO Mortality Database. Lancet Respir Med 2020;8:277-87. 10.1016/S2213-2600(19)30354-6 [DOI] [PubMed] [Google Scholar]
- 5.Lehnert P, Lange T, Møller CH, et al. Acute Pulmonary Embolism in a National Danish Cohort: Increasing Incidence and Decreasing Mortality. Thromb Haemost 2018;118:539-46. 10.1160/TH17-08-0531 [DOI] [PubMed] [Google Scholar]
- 6.Wendelboe AM, Raskob GE. Global Burden of Thrombosis: Epidemiologic Aspects. Circ Res 2016;118:1340-7. 10.1161/CIRCRESAHA.115.306841 [DOI] [PubMed] [Google Scholar]
- 7.Jiménez D, de Miguel-Díez J, Guijarro R, et al. Trends in the Management and Outcomes of Acute Pulmonary Embolism: Analysis From the RIETE Registry. J Am Coll Cardiol 2016;67:162-70. 10.1016/j.jacc.2015.10.060 [DOI] [PubMed] [Google Scholar]
- 8.Zhang Y, Chen Y, Chen H, et al. Performance of the Simplified Pulmonary Embolism Severity Index in predicting 30-day mortality after acute pulmonary embolism: Validation from a large-scale cohort. Eur J Intern Med 2024;124:46-53. 10.1016/j.ejim.2024.01.037 [DOI] [PubMed] [Google Scholar]
- 9.Yaman M, Orak M, Durgun HM, et al. The prognostic value of HALP score and sPESI in predicting in-hospital mortality in patients with pulmonary thromboembolism. Postgrad Med J 2024;101:60-5. 10.1093/postmj/qgae124 [DOI] [PubMed] [Google Scholar]
- 10.Roy PM, Penaloza A, Hugli O, et al. Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: the HOME-PE randomized trial. Eur Heart J 2021;42:3146-57. 10.1093/eurheartj/ehab373 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yamashita Y, Morimoto T, Amano H, et al. Validation of simplified PESI score for identification of low-risk patients with pulmonary embolism: From the COMMAND VTE Registry. Eur Heart J Acute Cardiovasc Care 2020;9:262-70. 10.1177/2048872618799993 [DOI] [PubMed] [Google Scholar]
- 12.Konstantinides SV, Meyer G, Becattini C, 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. 10.1093/eurheartj/ehz405 [DOI] [PubMed] [Google Scholar]
- 13.Piazza G. Advanced Management of Intermediate- and High-Risk Pulmonary Embolism: JACC Focus Seminar. J Am Coll Cardiol 2020;76:2117-27. 10.1016/j.jacc.2020.05.028 [DOI] [PubMed] [Google Scholar]
- 14.Murguia AR, Mukherjee D, Ojha C, et al. Reduced-Dose Thrombolysis in Acute Pulmonary Embolism A Systematic Review. Angiology 2024;75:208-18. 10.1177/00033197231167062 [DOI] [PubMed] [Google Scholar]
- 15.Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv 2015;8:1382-92. 10.1016/j.jcin.2015.04.020 [DOI] [PubMed] [Google Scholar]
- 16.Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol 2013;111:273-7. 10.1016/j.amjcard.2012.09.027 [DOI] [PubMed] [Google Scholar]
- 17.Melamed R, Tierney DM, Xia R, et al. Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study. Crit Care Med 2024;52:729-42. 10.1097/CCM.0000000000006162 [DOI] [PubMed] [Google Scholar]
- 18.Kiser TH, Burnham EL, Clark B, et al. Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism. Crit Care Med 2018;46:1617-25. 10.1097/CCM.0000000000003288 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Aykan AÇ, Gökdeniz T, Gül İ, et al. Reduced-Dose Systemic Fibrinolysis in Massive Pulmonary Embolism: A Pilot Study. Clin Exp Emerg Med 2023;10:280-6. 10.15441/ceem.23.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kjærgaard J, Carlsen J, Sonne-Holm E, et al. A randomized trial of low-dose thrombolysis, ultrasound-assisted thrombolysis, or heparin for intermediate-high risk pulmonary embolism-the STRATIFY trial: design and statistical analysis plan. Trials 2024;25:853. 10.1186/s13063-024-08688-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Beyer SE, Shanafelt C, Pinto DS, et al. National trends in utilization of thrombolytic therapy for acute pulmonary embolism. Vasc Med 2022;27:75-6. 10.1177/1358863X211048544 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sanchez O, Charles-Nelson A, Ageno W, et al. Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial. Thromb Haemost 2022;122:857-66. 10.1055/a-1653-4699 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest 2010;137:254-62. 10.1378/chest.09-0765 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Bigdelu L, Ebrahimi N, Maadarani O. Recurrent High-Risk Pulmonary Thromboembolism Treated with Repeated Thrombolytic Therapy Could be Helpful for Certain Patients: A Case Report and Review of the Literature. Eur J Case Rep Intern Med 2023;10:004042. 10.12890/2023_004042 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Freund Y, Cohen-Aubart F, Bloom B. Acute Pulmonary Embolism: A Review. JAMA 2022;328:1336-45. 10.1001/jama.2022.16815 [DOI] [PubMed] [Google Scholar]
- 26.Mardinger C, Boiteau PJE, Kortbeek JB. Thrombolysis of Postoperative Acute Pulmonary Embolism with a Thrombus in Transit. Case Rep Med 2020;2020:7561986. 10.1155/2020/7561986 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kainuma A, Ning Y, Kurlansky PA, et al. Deep vein thrombosis and pulmonary embolism after heart transplantation. Clin Transplant 2022;36:e14705. 10.1111/ctr.14705 [DOI] [PubMed] [Google Scholar]
- 28.Curtis GM, Lam SW, Reddy AJ, et al. Risk factors associated with bleeding after alteplase administration for pulmonary embolism: a case-control study. Pharmacotherapy 2014;34:818-25. 10.1002/phar.1440 [DOI] [PubMed] [Google Scholar]
- 29.Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041-6. 10.1164/rccm.200506-862OC [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Bae DH, Lee WJ, Shin YM. Incidence of Major Bleeding in Patients with Pulmonary Thromboembolism Treated with Fixed Dose Alteplase 100 mg. J Korean Med Sci 2020;35:e267. 10.3346/jkms.2020.35.e267 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Miller SE, Warach SJ. Evolving Thrombolytics: from Alteplase to Tenecteplase. Neurotherapeutics 2023;20:664-78. 10.1007/s13311-023-01391-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Crawford J, Roe A, Brumit J, et al. Tenecteplase Versus Alteplase: A Comparison of Bleeding Outcomes in Massive Pulmonary Embolism (TACO-PE). Ann Pharmacother 2025;59:232-7. 10.1177/10600280241271264 [DOI] [PubMed] [Google Scholar]
- 33.Li S, Gu HQ, Li H, et al. Reteplase versus Alteplase for Acute Ischemic Stroke. N Engl J Med 2024;390:2264-73. 10.1056/NEJMoa2400314 [DOI] [PubMed] [Google Scholar]
- 34.Zhou XY, Chen HL, Ni SS. Red cell distribution width in predicting 30-day mortality in patients with pulmonary embolism. J Crit Care 2017;37:197-201. 10.1016/j.jcrc.2016.09.024 [DOI] [PubMed] [Google Scholar]
- 35.Morillo R, Jiménez D, Bikdeli B, et al. Refinement of a modified simplified Pulmonary Embolism Severity Index for elderly patients with acute pulmonary embolism. Int J Cardiol 2021;335:111-7. 10.1016/j.ijcard.2021.02.039 [DOI] [PubMed] [Google Scholar]
- 36.Bayley E, Brown S, Bhamber NS, et al. Fatal pulmonary embolism following elective total hip arthroplasty: a 12-year study. Bone Joint J 2016;98-B:585-8. 10.1302/0301-620X.98B5.34996 [DOI] [PubMed] [Google Scholar]
- 37.Pellegrini VD, Jr, Eikelboom JW, Evarts CM, et al. Randomised comparative effectiveness trial of Pulmonary Embolism Prevention after hiP and kneE Replacement (PEPPER): the PEPPER trial protocol. BMJ Open 2022;12:e060000. 10.1136/bmjopen-2021-060000 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Rehman A, Singh A, Sridhar P, et al. Association of race, ethnicity and insurance status with outcomes for patients with acute pulmonary embolism treated by PERT: a retrospective observational study. Respir Res 2024;25:259. 10.1186/s12931-024-02872-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Sathianathan S, Meili Z, Romero CM, et al. Racial and gender disparities in the management of acute pulmonary embolism. J Vasc Surg Venous Lymphat Disord 2024;12:101817. 10.1016/j.jvsv.2024.101817 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Bobadilla L, Scatularo CE, Antoniolli M, et al. Impact of Reperfusion on Clinical Outcomes in Patients with Intermediate-High Risk Pulmonary Embolism. Curr Probl Cardiol 2022;47:101308. 10.1016/j.cpcardiol.2022.101308 [DOI] [PubMed] [Google Scholar]
- 41.Prosperi-Porta G, Ronksley P, Kiamanesh O, et al. Prognostic value of echocardiography-derived right ventricular dysfunction in haemodynamically stable pulmonary embolism: a systematic review and meta-analysis. Eur Respir Rev 2022;31:220120. 10.1183/16000617.0120-2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Prosperi-Porta G, Solverson K, Fine N, et al. Echocardiography-Derived Stroke Volume Index Is Associated With Adverse In-Hospital Outcomes in Intermediate-Risk Acute Pulmonary Embolism: A Retrospective Cohort Study. Chest 2020;158:1132-42. 10.1016/j.chest.2020.02.066 [DOI] [PubMed] [Google Scholar]