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.#46;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.#46;CTED vs.#46;CTEPH among RPVO vs.#46;CTED vs.#46;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.#46;CTED vs.#46;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.
