Validation of SEARCH, a Novel Hierarchical Algorithm to Define Long-term Outcomes After Pulmonary Embolism

Pulmonary Embolism Clinical Trial

— ValidSEARCH  

Official title:

An Observational Cohort Study to Validate SEARCH, a Novel Hierarchical Algorithm to Define Long-term Outcomes After Pulmonary Embolism

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05568927
• Other study ID #: Inari-RG-2022-01
• Status: Enrolling by invitation
• Start date: November 15, 2022
• Est. completion date: September 2024

Study information

• Verified date: February 2024
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Potential outcomes after PE occur on a spectrum: complete recovery, exercise intolerance from deconditioning/anxiety, dyspnea from concomitant cardiopulmonary conditions, dyspnea from residual pulmonary vascular occlusion, chronic thromboembolic disease and chronic thromboembolic pulmonary hypertension. Although a battery of advanced diagnostic tests could distinguish each of those conditions, the yield of individual tests among all post- PE patients is low enough that routine testing of all PE patients is not typically performed. Although the various possible post-PE outcomes have enormous implications for patient care, they are rarely distinguished clinically. Perhaps for this reason, chronic conditions after PE are rarely (if ever) used as endpoints in randomized clinical trials of acute PE treatment.

The proposed project will validate a clinical decision tree to distinguish among the various discrete outcomes cost-effectively through a hierarchical series of tests with the acronym SEARCH (for symptom screen, exercise function, arterial perfusion, resting heart function, confirmatory imaging and hemodynamics). Each step of the algorithm sorts a subset of patients into a diagnostic category unequivocally in a cost-effective manner. The categories are mutually exclusive and collectively exhaustive, so that each case falls into one, and only one, category.

Each individual test used in the algorithm has been clinically validated in pulmonary embolism patients, including the cardiopulmonary exercise test (CPET) technique that the investigators developed and validated. However, the decision tree approach to deploying the tests has not yet been validated.

Aim 1 will determine whether the SEARCH algorithm will yield concordant post-PE diagnoses when multiple reviewers independently evaluate multiple cases (reliability).

Aim 2 will determine whether the post-PE diagnoses are stable, according to the SEARCH algorithm, between the first evaluation and the subsequent one six months later (validity).

Description:

Study Design Patients with acute pulmonary embolism (PE) receive follow-up care in participating University of California Alliance on Pulmonary Embolism (UCAPE) pulmonary embolism clinics according to the standards of care previously agreed to by the physicians within UCAPE network. At least three months after the onset of acute PE, the patient's physician presents a summary of the case during an on-line meeting without disclosing protected health information or other identifying information. Six designated evaluators independently categorize each patient into a diagnostic endpoint node according to the SEARCH criteria.

SEARCH criteria (positive = at least one criteria met)

Symptoms

• The modified Medical Research Council (mMRC) score on a specific day in the two weeks prior to the interview is one or more points higher than he/she recalls it was on a specific day in the two weeks prior to the PE.

• The patient does not feel fully recovered to the level that existed prior to the PE (e.g. reduced tolerance of athletic abilities), regardless of mMRC scores at the time of the interview and before the PE

Insufficient data: At the first (post-3-month) evaluation, if breathing comfort and exercise tolerance compared to the condition prior to the acute pulmonary embolism could not be ascertained, then the "S" parameter is marked "insufficient data." The patient is excluded from the first primary outcome and the secondary outcome analyses. At the second (6 months subsequent) evaluation, if breathing comfort and exercise tolerance compared to the condition prior to the acute pulmonary embolism could not be ascertained, then the "S" parameter is marked "insufficient data." The patient is be excluded from the second primary outcome and the secondary outcome analyses. If the patient died from pulmonary embolism or pulmonary vascular disease between the first and second evaluations, the patient is to be excluded from the second primary outcome analysis but included in the secondary outcome analyses.If the patient died between the first and second evaluations from a cause other than pulmonary embolism or pulmonary vascular disease, the patient is to be excluded from the second primary outcome and the secondary outcome analyses.

Exercise

• The patient did not reach anaerobic threshold (AT).

• The patient's peak O2 consumption (VO2) was less than (<) 80% of the predicted peak VO2.

• Ventilatory dead space (VD) to tidal volume (VT) ratio (VD/VT) at AT is greater than or equal to (>=) 0.27.

• VD (= VT * VD/VT) in mL at AT is greater than or equal to (>=) 1.35 * the ideal body weight in lbs (IBW).

• In the absence of a VD/VT estimate, the minute ventilation (VE) to CO2 production (VCO2) ratio (VE/VCO2) at AT is greater than (>) 30, which has a sensitivity of 94% and specificity of 48% for a VD/VT at AT greater than 30.

• The ratio of VO2 per heart beat (O2pulse) at AT to the O2pulse at rest (O2pulse_AT/O2pulse_rest) is less than (<) 2.6, which corresponds to stroke volume augmentation at AT of less than 27%.

Insufficient data: At the first evaluation, if S criteria were positive and the patient did not have a subsequent interpretable CPET, then the E parameter is marked "insufficient data." The patient is excluded from the first primary and secondary outcome analyses. At the second evaluation, if S criteria were positive and the patient did not have a subsequent interpretable CPET, then (1) if the S criteria had not worsened since the first time point (mMRC score had not increased), then the results of CPET from the first evaluation point is accepted as true for the second time point; or (2) if the S criteria had worsened (mMRC score increased) and a CPET was not subsequently performed, then the patient is excluded from the second primary outcome and the secondary analysis.

Arterial perfusion

• Planar ventilation: perfusion scanning (planar V:Q) disclosed one or more segmental or larger perfusion defects that do not have matching ventilation defects.

• Planar perfusion scanning (planar Q) disclosed one or more segmental or larger perfusion defects that do not correspond to opacities on chest radiograph or chest CT (performed simultaneously or within 30 days).

• Singe photon emission computer tomography ventilation: perfusion scanning (SPECT V:Q) disclosed one or more segmental or larger perfusion defects that do not have matching ventilation defects.

• SPECT V:Q disclosed one or more segmental or larger perfusion defects that do not correspond to opacities on chest radiograph or chest CT (performed simultaneously or within 30 days).

• The patient did not have an interpretable perfusion scan.

Insufficient data: At the first evaluation, if S and E criteria were positive and the patient did not have a subsequent interpretable perfusion scan, then the A parameter is marked "insufficient data." The patient is excluded from the first primary outcome and the secondary outcome analyses. At the second evaluation, if S and E criteria were positive and the patient did not have a subsequent interpretable perfusion scan, then (1) if the S criteria had not worsened since the first time point (mMRC score had not increased), then the results of the perfusion scan from the first evaluation point is accepted as true for the second time point; or (2) if S criteria had worsened (mMRC score increased) and a perfusion scan was not subsequently performed, then the A parameter is marked "insufficient data." The patient is excluded from the second primary outcome and the secondary analyses.

Resting echocardiography

• Peak tricuspid regurgitation velocity is greater than (>) 2.8 m/s.

• The right ventricle (RV) to left ventricle (LV) ratio (RV/LV) of basal diameters is greater than (>) 1.0.

• There is flattened intraventricular septum or abnormal septal motion.

• Acceleration time of pulmonary ejection is greater than (>) 105 ms or there is midsystolic notching.

• Early diastolic pulmonary regurgitation velocity is greater than (>) 2.2 m/s.

• Pulmonary artery (PA) diameter is greater than (>) 25 mm.

• Tricuspid annular plane systolic excursion (TAPSE) of less than (<) 17 mm.

• Fractional area contraction of RV less than (<) 35% on 4 chamber view.

Insufficient data: At the first evaluation, if S, E and A criteria were positive and the patient did not have a subsequent interpretable echocardiogram, then the R parameter is marked "insufficient data." The patient is excluded from the first primary outcome and the secondary outcome analyses. At the second evaluation, if S, E and A criteria were positive and the patient did not have a subsequent interpretable echocardiogram, then (1) if S criteria had not worsened since the first time point (mMRC score had not increased), then the results of the echocardiogram from the first evaluation point are accepted as true for the second time point; or (2) if S criteria had worsened (mMRC score increased) and an echocardiogram was not subsequently performed, then the R parameter is marked "insufficient data." The patient is excluded from the second primary outcome and the secondary outcome analyses.

Confirmatory imaging

• Smaller than normal caliber arteries contain filling defects

• Eccentric filling defects

• Anastomoses of bronchial arteries

• Right side enlargement

• Contracted lung regions

• Heterogeneous ("mosaic") lung perfusion

Insufficient data: At the first or the second evaluations, absence of interpretable confirmatory imaging (CT or pulmonary angiogram) does not cause the patient to be excluded from the final analysis.

Hemodynamics

• Mean pulmonary artery pressure (mPAP) greater than (>) 20 mmHg with pulmonary arterial wedge pressure less than or equal to (<=) 15 mmHg

• Pulmonary vascular resistance (PVR) greater than or equal to (>=) 3 Wood Units.

Insufficient data: At the first or the second evaluations, absence of right heart catheterization does not cause the patient to be excluded from the final analysis.

X criteria

• During exercise, the mPAP vs cardiac output (CO) slope (mPAP/CO slope) greater than (>) 3 mmHg·L-1·min-1.

• PVR during exercise greater than or equal to (>=) PVR at rest.

Insufficient data: At the first or the second evaluations, absence of right heart catheterization during exercise does not cause the patient to be excluded from the final analysis.

Six months after the first evaluation, the patient's physician presents the case again, along with any updated data, to the UCAPE reader group. Without knowledge of the consensus first evaluation score or the clinically assigned second evaluation score, each member of the UCAPE reader group in the meeting again independently categorizes the patient with a diagnostic endpoint node, using the same on-line scoring tool used for Aim 1. Aim 1 is further described in the Statistics Section under the first and second primary outcomes.

In the instance in which a patient dies after the first evaluation but before the second evaluation could be performed, the patient's physician reviews the case to determine if the death was more likely than not to be related to (1) PE or other pulmonary vascular disease; or (2) an alternative diagnosis.

Aim 2 will determine whether the post-PE diagnoses are stable, according to the SEARCH algorithm, between the first evaluation and the subsequent one (six additional months later). After the scoring procedure described in Aim 1, the mode of the score from the UCAPE readers will be recorded as the consensus score. Aim 2 is further described in the Statistics Section under the secondary outcome.

Quality Assurance

Data Validation

Study facilitators review presentations to ensure lack of protected health information. The presenters validate accuracy of information in the case presentations.

Data checks

A core group performs quality assurance (QA) reviews of test results for completeness, accuracy, uniformity and clarity of (deidentified) data necessary to categorize patients.

Source data verification

Presenters ensure that study data reflects the source data. The presenters will not disclose the patients' identities or any other protected health information to the study staff.

Data dictionary

Pulmonary Embolism - Medical Subject Heading (MeSH) definition Venous Thrombosis - MeSH definition Stroke volume augmentation (SVA): increase in ventricular stroke volume during exercise, compared to stroke volume at rest Physiological dead space proportion (VD/VT): proportion of the ventilatory air in which gas exchange does not occur Chronic thromboembolic disease (CTED): pulmonary hypertension only during exercise due to intravascular pulmonary arterial scars after acute pulmonary embolism Chronic thromboembolic pulmonary hypertension (CTEPH): pulmonary hypertension due to intravascular pulmonary arterial scars after acute pulmonary embolism Symptomatic residual pulmonary vascular occlusion (RPVO): dyspnea or exercise intolerance with objective evidence of segmental or larger mismatched perfusion defects Symptomatic residual pulmonary vascular occlusion with increased VD/VT (RPVO_VD/VT): RPVO with higher-than-normal VD/VT Symptomatic residual pulmonary vascular occlusion with decreased SVA (RPVO_SVA): RPVO with lower-than-normal SVA Symptomatic residual pulmonary vascular occlusion with increased VD and decreased SVA (RPVO_VD+SVA): RPVO with higher-than-normal VD/VT and lower-than-normal SVA Symptomatic residual pulmonary vascular occlusion not otherwise specified (RPVONOS): RPVO with unspecified physiological effect

Standard Operating Procedure Outline

Presenters review all cases in their UCAPE pulmonary embolism follow-up clinics who meet the inclusion criteria. The presenters and a quorum of at least four evaluators independently grade cases.

Missing data

Data that are unavailable, non-reported, uninterpretable, or considered missing because of data inconsistency or out-of-range results will be marked as "missing."

Statistical analysis and sample size estimates

Primary outcome sample size

Fleiss' kappa statistic will measure agreement among the multiple reviewers about the clinical group designation (1-5) for the first evaluation point. The agreement among interpretations will be graded with commonly accepted criteria for kappa values.

Up to six readers review and score cases. Potential outcomes are grouped into five clinically related groups with the following expected probabilities of occurrence:

Symptomatic recovery (59%)

Dyspnea without CPET defects or dyspnea from alternative diagnoses (19%)

Not distinguished among RPVO vs CTED vs CTEPH among RPVO vs CTED vs CTEPH (14%)

RPVO or CTED (13%)

CTEPH (4%).

The expected kappa will be 0.75. With these assumptions, a validation sample set of n = 150 would produce a lower 95% confidence interval (CI) of 0.7 with an alpha of 0.05.

Secondary outcome sample size

For the secondary outcome, we will group the outcomes into six clinically related groups (pi-x), with the sixth group representing death attributed to PE or pulmonary vascular disease:

Symptomatic recovery

Dyspnea without CPET defects or dyspnea from alternative diagnoses or death from alternative diagnoses

Not distinguished among RPVO vs CTED vs CTEPH

RPVO or CTED

CTEPH

Death from PE, CTEPH or other pulmonary vascular disease.

The investigators expect that more than 90% of patients will remain in the same diagnostic group between the first evaluation and the second evaluation. The investigators anticipate that a study size of 150 would disclose 90% agreement and exclude with 95% confidence agreement in fewer than 15% of patients.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 150
• Est. completion date: September 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• age 18 years or greater

• objective evidence of acute pulmonary thrombo-embolism at least six months before the evaluation

• anticipated survival for at least three months

• a diagnostic endpoint in the SEARCH algorithm has been reached.

Exclusion Criteria:

? Cases in which the clinical presentations contain insufficient interpretable data to permit evaluation of SEARCH criteria, as described in the Study Design section, will be excluded from the analysis.

Related Conditions & MeSH terms

• Chronic Thromboembolic Pulmonary Hypertension
• Embolism
• Hypertension, Pulmonary
• Pulmonary Embolism

Intervention

Other:
• SEARCH algorithm
The SEARCH algorithm is a structured, stepwise approach to follow up testing after acute PE that will enable timely diagnosis of post PE sequelae. The test results at each step inform the performance of the subsequent steps. The order of the tests in the algorithm uses the acronym SEARCH: Symptom screen, exercise function, arterial perfusion, resting heart function, confirmatory imaging, and hemodynamics.

Locations

Country	Name	City	State
United States	University of California, San Francisco-Fresno	Fresno	California
United States	University of California, Irvine	Irvine	California
United States	University of California, Los Angeles	Los Angeles	California
United States	University Hospital, Riverside	Moreno Valley	California
United States	University of California, Davis	Sacramento	California
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	University of California, Los Angeles - Harbor	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Diego	Inari Medical

Country where clinical trial is conducted

United States, 

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Wan T, Rodger M, Zeng W, Robin P, Righini M, Kovacs MJ, Tan M, Carrier M, Kahn SR, Wells PS, Anderson DR, Chagnon I, Solymoss S, Crowther M, White RH, Vickars L, Bazarjani S, Le Gal G. Residual pulmonary embolism as a predictor for recurrence after a first unprovoked episode: Results from the REVERSE cohort study. Thromb Res. 2018 Feb;162:104-109. doi: 10.1016/j.thromres.2017.11.020. Epub 2017 Dec 8. — View Citation

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Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Interobserver agreement among readers regarding the clinical condition during the first evaluation point: at least three months after acute PE.	Based on a structured evaluation of clinical data generated during long term follow-up after PE and presented in a de-identified manner, six observers will independently categorize each patient as one of the following: complete recovery from dyspnea and exercise intolerance to the state that pre-existed PE or dyspnea after PE but cardiopulmonary exercise test showing normal ventilatory dead space proportions (VD/VT) and normal estimated stroke volume augmentation (SVA) during exercise; dyspnea after PE likely due to alternative diagnoses; dyspnea after PE with increased VD/VT or decreased SVA during exercise in the presence of residual pulmonary vascular occlusion (RPVO) but without hemodynamic measurement; symptomatic RPVO or chronic thromboembolic disease (CTED) documented by hemodynamic measurement; chronic thromboembolic pulmonary hypertension (CTEPH) documented by hemodynamic measurement.	Each presentation will summarize clinical data leading up to and including an assessment time point at least 3 months after the onset of acute PE
Primary	Interobserver agreement among readers regarding clinical condition at the second evaluation point.	Based on a structured evaluation of clinical data generated during long term follow-up after PE and presented in a de-identified manner, six observers will independently categorize each patient as one of the following: complete recovery from dyspnea and exercise intolerance to the state that pre-existed PE or dyspnea after PE but cardiopulmonary exercise test showing normal VD/VT and normal estimated SVA during exercise; dyspnea after PE likely due to alternative diagnoses; dyspnea after PE with increased VD/VT or decreased SVA during exercise in the presence of RPVO but without hemodynamic measurement; symptomatic RPVO or CTED documented by hemodynamic measurement; CTEPH documented by hemodynamic measurement; death prior to the evaluation point.	Each presentation will summarize clinical data leading up to and including an assessment time point at least 6 months after the first assessment (described under Aim 1a)
Secondary	Constancy of diagnosis between first evaluation point and second evaluation point	Constancy of diagnosis will be defined as the proportion of patients whose diagnostic category is the same between the first and the second evaluation time points.; The diagnostic category for the first time point will be the mode of the diagnostic category scores selected by the reviewers among the five options listed for "Outcome 1."; The diagnostic category for the second time point will be the mode of the diagnostic category scores selected by the reviewers among the six options listed for "Outcome 2."; Constancy of diagnosis will be calculated as the number of patents with the same diagnoses at the first and second time points divided by the total number of patients who were evaluated at the first and second time points.	Stability between the two time points will be determined after the presentation and evaluation of the 12-month time point