Repeated Examinations for Typing Pulmonary Embolism

BACKGROUND

Pulmonary embolism (PE) is the third most common acute cardiovascular condition and remains associated with substantial morbidity and mortality. Although advances in therapy have reduced overall mortality, optimal treatment within the intermediate-high risk group remains uncertain. In parallel, knowledge of long-term outcomes after PE in Sweden is incomplete, largely due to the absence of a dedicated national PE registry.

Risk stratification of PE has evolved into the current four-tier European Society of Cardiology (ESC) classification, supported by clinical risk scores such as the Pulmonary Embolism Severity Index (PESI). The intermediate-high risk group is especially challenging due to marked heterogeneity in clinical course, ranging from rapid recovery to sudden deterioration. Existing risk scores were mainly developed to identify low risk patients and provide limited guidance on predicting deterioration, largely due to low positive predictive value.

Current risk stratification relies on static, single-timepoint variables, despite PE being a dynamic disease. Prospective studies evaluating the early temporal course of PE are scarce and typically focus on isolated parameters, with no studies integrating repeated clinical, imaging, and biomarker assessments.

The RE-TyPE study aims to address these gaps by characterizing the early clinical course of intermediate-high risk PE and linking this to short- and medium-term outcomes. The study will also provide a platform for long-term follow-up, evaluation of treatment strategies, and a research infrastructure dedicated to all PE at Sahlgrenska University Hospital.

AIM, OBJECTIVES AND METHODS

The overarching research aim is to characterize the early clinical course of intermediate-high risk PE to identify phenotypes associated with poor outcome (Cohort A), and to investigate intermediate- and long-term outcome and outpatient care for all PE cases at Sahlgrenska University Hospital (Cohort B).

PRIMARY OBJECTIVES

Cohort A - prospective phenotyping (admitted intermediate-high risk PE):

To collect in-dept data regarding the early clinical course of PE, including temporal changes in vital signs, ECG, echocardiography and biomarkers from baseline (day 0, PE-event) until day 2, and to analyse its association with in-hospital clinical outcome day 0-7.

Cohort B - follow-up (all PE):

To collect in-dept baseline data, including vital signs, ECG, echocardiography and biomarkers, and to analyse its association with intermediate and long-term outcome (>12 months)

SCEONDARY OBJECTIVES

Cohort A - prospective phenotyping:

• To collect in-dept data regarding the early clinical course of PE, including temporal changes in vital signs, ECG, echocardiography and biomarkers from baseline (day 0, PE-event) until day 2, and to analyse its association with clinical outcome at day 30
• To examine the timing of thrombolysis and/or thrombectomy in relation to in-hospital (day 0-7), short-term (day 30) and medium-term (~90 days) outcome
• To investigate the association between simple walking test with pulse oximetry, sit-to-stand test (drop of saturation, heartrate) or 6-minute walking test (walking distance, drop of oxygen saturation and heart rate) and clinical outcomes within 7, 30 and ~90 days respectively
• To investigate the value of in-hospital simple walking test with pulse oximetry in predicting clinical outcomes in-hospital (day 0-7), short-term (day 30) and medium-term (~90 days) outcome
• To investigate the correlation between radiological signs of right ventricular strain (increased right ventricle/left ventricle, RV/LV, -ratio and echocardiographic signs of right ventricular strain

Cohort B - registry (all PE)

B. Cohort B - follow-up (all PE)

• Evaluate prognostic implications of clinical phenotypes (based on clinical course for cohort A and based on baseline variables for cohort B) by assessing associations with long-term (1-year) patient-reported outcome measures (PROMs) according to the Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL), Post Vte Functional Scale (PVFS) or EuroQol 5-Dimension (EQ5D) questionnaire.
• Evaluate prognostic implications of clinical phenotypes (based on clinical course day 0-2 for cohort A and based on baseline variables day 0 for cohort B) by assessing associations with long-term (1-year) outcome including CTEPH as well as mortality, recurrent VTE and bleeding.
• To assess admission rate and outcome for low risk symtomatic and low risk incidental PE

STUDY DESIGN

The RE-TyPE study combines two observational study approaches:

A) A prospective observational cohort study of hospitalized patients with intermediate-high risk PE

and

B) A follow-up cohort including all patients diagnosed with PE at Sahlgrenska University Hospital.

Prospective observational study (Cohort A)

Hospitalized patients with intermediate-high risk PE at any of the three sites of Sahlgrenska University Hospital (Sahlgrenska, Östra or Mölndal) are eligible for inclusion within 48 hours of PE event (patients included 24-48 hours post PE will be considered late inclusions and will enter the study at day 1). This constitutes patients presenting with primary PE as well as patients who are admitted for other causes and suffer from PE while admitted. Inclusion will be performed Mondays to Fridays.

After verbal and written informed consent, the patient will be included in RE-TyPE cohort A and undergo serial repeated examinations day 0 (admission), day 1 (24 ± 6h) and day 2 (48 ± 12h), including vital parameters; pharmacologic treatment including oxygen therapy, thrombolysis and thrombectomy; respiratory and circulatory support; echocardiography, ECG, laboratory blood work-up, blood samples for biobanking, complications and outcome.

The majority of examinations will be performed at the hospital ward where the patient is admitted. Full echocardiographic evaluation at baseline (day 0) will be performed at the department of Clinical Physiology whereas follow-up echocardiographic examinations day 1 and 2 will be performed bedside (Point Of Care UltraSound, POCUS) at the ward where the patient is admitted. Follow-up will be scheduled to 30 (± 48h) and approximately day 90 (routine clinical follow-up).

PE follow-up cohort (Cohort B)

Cohort B constitutes all PE patients diagnosed at Sahlgrenska University Hospital. Therefore, all patients in Cohort A are also included in Cohort B. Patients only included in Cohort B (i.e. not existing in Cohort A) are patients with low, intermediate-low or high risk PE, or patients with intermediate-high risk PE who were not identified for inclusion (i.e. missed cases eligible for Cohort A).

PE patients discharged from the emergency department (ED) or admitted low-risk PE may be included in Cohort B after informed consent during ED visit or hospitalization. However, they will mainly be included at their outpatient follow-up visit (provided they are alive and registered as living within the area covered by Sahlgrenska University Hospital). Only patients in Cohort A will be subjected to the prospective serial evaluations explained above. The PE patients outside of Cohort A will be "follow-up only" patients. For these patients, only baseline day 0, day 90 and long-term variables will be collected.

Cancer associated PE

Patients who suffer from PE during active oncologic treatment are managed by the Department of Oncology at Sahlgrenska University Hospital. Aside from the oncologic treatment, the oncology department also handles the treatment and follow-up of the PE (sometimes in collaboration with consults at the internal medicine department). To bridge this gap, we will establish a collaboration with the oncology department regarding RE-TyPE, which will involve a specific contact person at the Department of Oncology regarding this study. Patients with cancer associated PE are eligible for inclusion in Cohort A or B.

Analytical and statistical considerations

The clinical course (PE phenotype) during day 0-2 will be characterized by recovery or persistence of right ventricular dysfunction, ECG changes, and biomarker levels. Right ventricular function will be assessed by TAPSE and RV/LV ratio; ECG findings include septal T-wave inversions, S1Q3T3 pattern, and right axis deviation; biomarkers include lactate, NT-proBNP and troponin I.

Because measurements are repeated over time, mixed-effects models will be used to estimate average levels and trajectories. Linear mixed models will be applied for continuous variables and generalized mixed models for binary variables.

Associations between phenotype (early clinical course day 0-2) and subsequent outcome (day 2-7) will be analysed using joint models combining mixed-effects models with Cox regression. Multivariable models will adjust for baseline confounders including age, sex, PE risk class, cancer, thrombus burden and reperfusion therapy.

The sample size will be based on the association between clinical course and the primary clinical outcome (clinical deterioration). In Cohort A, the expected 7-day deterioration is approximately 10%. The sample size calculation is based on a binary predictor (e.g. "severe clinical phenotype" yes or no), and an expected 6% vs 14% clinical deterioration proportion in the non-severe vs severe group (corresponding to 10% total outcome). Using a two-sided α = 0.05, 80% power, and an expected hazard ratio (HR) of approximately 2.5 the required sample size would be slightly over 350 patients. Adding the possibility of 10-15% of the events occurring before day two, 400 patients would be an optimal sample size (https://riskcalc.org/samplesize/).

CENTRAL DEFINITIONS

Main definitions

• Low risk PE: Hemodynamic stable, normal right ventricular function, cardiac biomarkers normal/low (clinical risk scores low)
• Intermediate-low risk PE: Hemodynamic stable, either right ventricular dysfunction or positive cardiac biomarkers
• Intermediate-high risk PE: Hemodynamic stable, right ventricular dysfunction and positive cardiac biomarkers
• High risk PE: Hemodynamic instability, right ventricular dysfunction and positive cardiac biomarkers
• Hemodynamic instability: Systolic BP < 90 mmHg for >15 minutes, or need for vasopressors, or Signs of shock
• ISTH definition for major bleeding: Clinically overt bleeding that is fatal; or occurs in a critical area or organ; or is associated with a fall in haemoglobin of >20 g/L; or leading to transfusion of ≥ 2 units of blood.

PRELIMINARY RESULTS

Within in the intermediate-high risk group of PE, current ESC risk stratification method, combining right ventricular dysfunction with biomarkers suggesting myocardial injury, has insufficient positive predictive value to detect who will deteriorate or not. No markers in isolation or in combination have proven sufficient to predict which patients will deteriorate. Risk prediction tools such PESI has also displayed low positive predictive value for detecting patients who will need more advanced treatment. This further emphasizes the relevance of the RE-TyPE project.

The RE-TyPE protocol is finalized and the study has recieved ethical approval from the Swedish Ethical Review Authority (approval number 2026-00503-01).

ETHICAL CONSIDERATIONS

Patients will be included after verbal and written informed consent. The principal investigators and co-investigators (physicians as well as nurses) involved in the study may include patients. The added examinations outside of clinical routine carry no risk for serious adverse events. The study has been ethically approved and will be conducted in accordance with the declaration of Helsinki. Contact has been established with Gothia Forum regarding this specific project for quality assurance.

SCIENTIFIC IMPORTANCE

RE-TyPE is the first study to perform serial investigations using multiple modalities to phenotype PE. This approach with serial investigations of intermediate-high risk PE enables a unique possibility of linking high resolution clinical phenotyping with early, intermediate and long-term outcome. There are numerous studies on single time-point predictors. In contrast to these static measurements, RE-TyPE captures dynamic disease patterns, enabling identification of distinct clinical phenotypes defined by their trajectories rather than static measurements. Also, the follow-up part of RE-TyPE (Cohort B) provide knowledge regarding intermediate- and long-term outcome and enables evaluation of the regional outpatient clinical care of PE patients. If successful, the RE-TyPE-study could significantly improve the quality and safety of care for PE patients.

Inclusion criteria

• Adult patients (≥ 18 years old) who is diagnosed with, or followed as out-patients for, PE at Sahlgrenska University Hospital
• Written informed consent

Exclusion criteria

from Cohort A:

• Low risk, intermediate-low risk or high risk PE*
• >48 hours since arrival to hospital
• Expected inability to comply with the protocol (e.g. dementia)

There are no exclusion criteria from Cohort B. Patients in Cohort B who are not part of Cohort A may be included at diagnosis (day 0) or at follow-up (~day 90).

*If biomarkers (and/or echocardiography) are not available in hemodynamically stable patients, RV/LV-ratio >1 will be considered as preliminary intermediate-high risk. If biomarkers later fall out negative, the patient will be considered as intermediate-low risk and will be moved to Cohort B