Effectiveness of pharmacological thrombolysis on clinical outcomes in high-risk pulmonary embolism patients with extracorporeal membrane oxygenation: a nationwide inpatient database study

Abstract

Background

Current guidelines recommend systemic thrombolysis as the first-line reperfusion treatment for patients with high-risk pulmonary embolism (PE) who present cardiogenic shock but do not require extracorporeal membrane oxygenation (ECMO). However, little is known about the optimal reperfusion treatment in high-risk PE patients requiring ECMO. We aimed to evaluate whether pharmacological thrombolysis improved high-risk PE patients’ outcomes who received ECMO.

Methods

This was a retrospective cohort study using the Japanese Diagnosis Procedure Combination inpatient database from April 2010 to March 2021. We identified patients who were diagnosed with PE and received ECMO on the day of admission. Patients who received pharmacological thrombolysis on the same day of ECMO initiation were defined as the thrombolysis group, and the remaining patients as the control group. The primary outcome was in-hospital mortality and secondary outcomes were favourable neurological outcomes, length of the hospital stay, length of the ECMO, total hospitalization cost, major bleeding, and blood transfusion volume. Propensity-score inverse probability of treatment weighting (IPTW) was performed to compare the outcomes between the groups.

Results

Of 1,248 eligible patients, 391 (31%) received pharmacological thrombolysis on the same day of ECMO initiation. Among the unweighted cohort, patients in the thrombolysis group were less likely to have poor consciousness at admission, out-of-hospital cardiac arrest, and left heart catheterization. After IPTW, the patient characteristics were well-balanced between the two groups The crude in-hospital mortality was 52% in the thrombolysis group and 59% in the control group. After IPTW, in-hospital mortality did not differ significantly between the two groups (risk difference: -2.1%, 95% confidence interval: -8.6–4.3%). There were also no significant differences in the secondary outcomes including the favourable neurological outcomes, length of hospital stay, length of ECMO, total hospitalization cost, major bleeding, and blood transfusion volume.

Conclusions

Pharmacological thrombolysis was not associated with a reduced in-hospital mortality or increased major bleeding in the high-risk PE patients receiving ECMO.

Background

Acute pulmonary embolism (PE) is the most serious clinical manifestation of venous thromboembolism and is associated with substantial morbidity and mortality [1, 2]. The risk of acute PE is classified into low, intermediate, and high, depending on the risk of early death based on the haemodynamic instability, right ventricular dysfunction, and comorbidities [3]. High-risk PE is an immediately life-threatening situation defined by haemodynamic instability, including cardiac arrest, obstructive shock, or persistent hypotension [3]. Among these patients with a haemodynamic compromise requiring extracorporeal membrane oxygenation (ECMO), in-hospital mortality was quite high at approximately 62% [4, 5].

Current guidelines recommend systemic pharmacological thrombolysis as the first-line reperfusion treatment for patients with high-risk PE [3]. However, this recommendation is mainly based on evidence regarding PE patients with cardiogenic shock not requiring ECMO [6], and little is known about the optimal reperfusion treatment in high-risk PE patients requiring ECMO. There are no randomized controlled trials in high-risk PE patients requiring ECMO due to the nature of the patient population with life-threatening conditions. Only two previous observational studies including patients with surgical embolectomy partially assessed the effect of pharmacological thrombolysis in combination with ECMO on in-hospital mortality, and they showed inconsistent results [5, 7]. To our knowledge, no previous studies have focused on the effect of pharmacological thrombolysis in combination with ECMO on in-hospital mortality.

The present study, therefore, aimed to evaluate the effect of pharmacological thrombolysis on in-hospital mortality and other clinical outcomes including the neurologic outcomes, hospitalization cost, and bleeding events in high-risk PE patients who received ECMO, using a nationwide inpatient database in Japan.

Methods

Results

During the study period, we identified 1,248 eligible patients (Fig. 1). Of those, 391 (31%) received pharmacological thrombolysis on the same day of ECMO initiation and were allocated to the thrombolysis group. Of the 391 patients in the thrombolysis group, 271 received monteplase, 103 received urokinase, and 17 received both monteplase and urokinase on the same day of ECMO initiation. Of the 857 patients in the control group, 89 received pharmacological thrombolysis after the day of ECMO initiation.

Table 1 shows the patient characteristics. Among the unweighted cohort, patients in the thrombolysis group were less likely to have poor consciousness at admission, out-of-hospital cardiac arrest, and left heart catheterization. After IPTW, the patient characteristics were well-balanced between the two groups (Fig. 2). The propensity score distribution between the two groups was adequately balanced after IPTW (Additional file 1: Fig. S1 and Fig. S2).

Table 2 shows the outcomes in the unweighted and weighted cohorts. The crude in-hospital mortality was 52% in the thrombolysis group and 59% in the control group. After IPTW, there was no significant difference in in-hospital mortality between the two groups (risk difference: -2.1%, 95% confidence interval: -8.6–4.3%). There were also no significant differences in the secondary outcomes including the favourable neurological outcomes, length of hospital stay, length of ECMO, total hospitalization cost, major bleeding, and blood transfusion volume.

Table 2. Results of inverse probability of treatment weighting in the unweighted and weighted cohorts

CI, confidence interval; ECMO, extracorporeal membrane oxygenation; SD, standard deviation

Table 3 shows the results of the subgroup analyses in the weighted cohort. There were no significant differences in in-hospital mortality as well as the secondary outcomes.

Table 3. Results of the subgroup analyses in the weighted cohort

CI, confidence interval; ECMO, extracorporeal membrane oxygenation; SD, standard deviation

Discussion

The present study showed no significant association between pharmacological thrombolysis and in-hospital mortality or the other clinical outcomes (neurologic outcomes, hospitalization cost, or bleeding events) in high-risk PE patients who received ECMO. These findings were consistent in the subgroup analyses in the patients with and without cardiopulmonary resuscitation on the day of admission.

Unlike our results, a recent large study that included 2,197 high-risk PE patients with ECMO using a nationwide inpatient database in Germany showed that thrombolysis in combination with ECMO was associated with a lower risk of in-hospital mortality (odds ratio, 0.60 [95% confidence interval, 0.43–0.85]) The study was adjusted only for age, sex, and comorbidities [5]. However, the present results showed that the control group was likely to have more severe clinical presentations such as poor consciousness or out-of-hospital cardiac arrest as compared to the thrombolysis group, suggesting that the effect of thrombolysis in the previous study could have been overestimated.

ECMO alone restores haemodynamics with right ventricular unloading and adequate tissue oxygenation [18]. During about four days of haemodynamic stabilization carried out by ECMO, heparin-induced endogenous thrombolysis usually allows for weaning from ECMO support [18, 19]. Additional pharmacological thrombolysis may shorten ECMO duration, because the present study showed a trend toward a shorter ECMO duration in the thrombolysis group as compared to the control group. However, a shorter ECMO duration was not associated with a lower in-hospital mortality.

In the present study, there were no significant differences in major bleeding as well as blood transfusion volume between the thrombolysis and control groups. It may be safely feasible to add pharmacological thrombolysis in high-risk PE patients who received ECMO but still had haemodynamic compromise or early recurrent PE, unless accompanied by bleeding complications. Further investigations are needed to determine the optimal thrombolytic agent and dosage in combination with ECMO.

The present study had several strengths. First, the present study was based on one of the largest databases, which covered approximately 90% of all tertiary emergency hospitals in Japan. Second, the present study focused not only on the qualitative assessment of the presence or absence of major bleeding but also on the quantitative assessment of blood transfusion volume.

The present study had several limitations. First, the decision on whether to use pharmacological thrombolysis was at the individual clinician’s discretion due to the nature of the present study using the observational database, which led to confounding by indication. We attempted to control for this confounding by indication using the IPTW. However, we were unable to control for any possible unmeasured variables, such as vital signs or laboratory data. Second, the present study was unable to identify whether patients received ECMO after failing pharmacological thrombolysis or whether they initially received ECMO and then pharmacological thrombolysis on the day of admission. Third, the incidence of major bleeding events in the present study was considerably lower than in the previous German study (intracranial bleeding, 1.2% vs. 4.9%) [5] and other previous studies [7, 20]. Given that the sensitivity of the diagnosis might have been low in our database [21], there was a possibility of underreporting in the major bleeding events. Fourth, 31% of the thrombolytic agents in the present study were urokinase, suggesting caution should be taken when applying our results to those in other countries where t-PA is the main thrombolytic agent [22]. Finally, using the JCS status at discharge might not be suitable to define whether there were favourable or unfavourable neurological outcomes as compared to the CPC or modified Rankin Scale, which were commonly used in previous studies [23].

Conclusions

The present study using a nationwide inpatient administrative database showed that the use of pharmacological thrombolysis was not associated with a reduced in-hospital mortality as well as increased major bleeding in high-risk PE patients who received ECMO.

Abbreviations

Declarations

Ethics approval and consent to participate: This study was performed in accordance with the amended Declaration of Helsinki, and the Institutional Review Board of The University of Tokyo approved this study (approval number: 3501-(3); 25 December 2017).

Consent for publication: The review board waived the requirement for informed consent because of the anonymous nature of the data. No information describing individual patients, hospitals, or treating physicians was obtained.

Availability of data and materials: The datasets analysed during the current study are not publicly available owing to contracts with the hospitals providing the data to the database.

Competing interests: The authors declare that they have no conflict of interest.

Funding: This research was funded by grants from the Ministry of Health, Labour and Welfare, Japan, grant numbers 19AA2007 and H30-Policy-Designated-004, and the Ministry of Education, Culture, Sports, Science and Technology, Japan, grant number 17H04141.

Authors’ contributions: Yuji Nishimoto: Conceptualization, Software, Formal analysis, Investigation, Writing - Original Draft; Hiroyuki Ohbe: Conceptualization, Methodology, Software, Formal analysis, Investigation, Writing - Review and Editing; Hiroki Matsui: Software, Formal analysis, Investigation, Data Curation; Mikio Nakajima: Conceptualization, Investigation, Writing - Review and Editing, Supervision; Yusuke Sasabuchi: Conceptualization, Investigation, Writing - Review and Editing, Supervision; Tetsuya Watanabe: Software, Investigation, Resources, Supervision; Takahisa Yamada: Software, Investigation, Resources, Supervision; Masatake Fukunami: Software, Investigation, Resources, Supervision; Hideo Yasunaga: Writing - Review and Editing, Supervision. All authors read and approved the final manuscript.

Acknowledgments: We would like to express our gratitude to Mr. John Martin for his grammatical assistance.

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