414 | Acad Emerg Med. 2025;32:414–425.wileyonlinelibrary.com/journal/acem
Received: 30 July 2024 | Revised: 14 October 2024 | Accepted: 21 October 2024
DOI: 10.1111/acem.15046
O R I G I N A L A R T I C L E
Failure rate of the pulmonary embolism rule-out criteria
rule for adults 35 years or younger: Findings from the RIETE
Registry
Thibaut Jossein MD1 | Lucia Mazzolai MD, PhD2 | Alicia Lorenzo Hernández MD, PhD3 |
Sonia Otálora Valderrama MD, PhD4 | Marija Zdraveska MD5 | Agustina Rivas Guerrero MD6 |
Antonio López Ruiz MD7 | Pierpaolo Di Micco MD, PhD 8 | Manuel Monreal MD, PhD9,10 |
Olivier Hugli MD, MPH1 | the RIETE Investigators
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Author(s). Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.
See related article on page 476 and 480.
A full list of RIETE investigators is given in Appendix S1.
Supervising Editor: Alice M. Mitchell
1Department of Emergency Medicine,
Lausanne University Hospital, Lausanne,
Switzerland
2Department of Angiology, Lausanne
University Hospital, Lausanne,
Switzerland
3Department of Internal Medicine, Hospital
Universitario La Paz, Madrid, Spain
4Department of Internal Medicine,
Hospital Universitario Virgen de Arrixaca,
Murcia, Spain
5PHI University Clinic of Pulmology and
Allergy Skopje, Skopje, Republic of North
Macedonia
6 Department of Pneumonology, Hospital
Universitario Donostia, San Sebastián,
Guipúzcoa, Spain
7 Department of Internal Medicine,
Hospital de la Axarquía, Málaga, Spain
8 Department of Internal Medicine and
Emergency Room, Presidio Ospedaliero S.
Maria Delle Grazie, Naples, Italy
9Faculty of Health Sciences, Universidad
Católica San Antonio de Murcia (UCAM),
Murcia, Spain
10CIBER Enfermedades Respiratorias
(CIBERES), Madrid, Spain
Correspondence
Prof Olivier Hugli, Emergency
Department, Lausanne University
Hospital, BH 09-777, Bugnon 46, 1011
Lausanne, Switzerland.
Email: olivier.hugli@chuv.ch
Abstract
Background: The use of a computed tomography pulmonary angiogram to diagnose
pulmonary embolism (PE) has increased, leading not only to higher PE diagnoses but
also to overdiagnosis and unnecessary radiation exposure, even in young patients de-
spite a lower PE incidence. The aim of this study was to assess the failure rate of the
pulmonary embolism rule-out criteria 35 (PERC-35) rule developed to reduce unnec-
essary testing in individuals aged ≤35 years among patients included in the Registro
Informatizado de la Enfermedad TromboEmbolica Venosa (RIETE) Registry.
Methods: This retrospective cohort study used data from the RIETE Registry, an on-
going, international prospective registry of patients with objectively confirmed ve-
nous thromboembolism. The primary outcome was the missed PE rate using PERC-35
criteria. Secondary outcomes included the comparison of demographic and clinical
characteristics, PE localization, treatment strategies, and outcomes between PERC-
negative (PERC-35N) versus PERC-positive (PERC-35P) patients.
Results: Of 58,918 adult patients with acute PE, the PERC-35 rule demonstrated a
low missed PE rate of 0.35% (n = 204), with an upper 95% confidence interval [CI]
of 0.40%. The missed rate was 7.0% (95% CI 6.0%–7.9%) in the 18- to 35-year sub-
group. Compared to PERC-35P patients, PERC-35N patients were younger (mean age
28.4 years), with a lower body mass index, and included a higher proportion of preg-
nant/postpartum women. PERC-35N patients had a significantly lower rate of chronic
diseases and presented less frequently with dyspnea or syncope but more often with
chest pain. They showed lower rates of positive D-dimer and troponin levels. PERC-
35N patients experienced fewer major bleeding episodes, similar recurrence rates of
PE/deep vein thrombosis, and no deaths during anticoagulation.
Received: 30 July 2024 | Revised: 14 October 2024 | Accepted: 21 October 2024
DOI: 10.1111/acem.15046
O R I G I N A L A R T I C L E
Failure rate of the pulmonary embolism rule-out criteria
rule for adults 35 years or younger: Findings from the RIETE
Registry
Thibaut Jossein MD1 | Lucia Mazzolai MD, PhD2 | Alicia Lorenzo Hernández MD, PhD3 |
Sonia Otálora Valderrama MD, PhD4 | Marija Zdraveska MD5 | Agustina Rivas Guerrero MD6 |
Antonio López Ruiz MD7 | Pierpaolo Di Micco MD, PhD 8 | Manuel Monreal MD, PhD9,10 |
Olivier Hugli MD, MPH1 | the RIETE Investigators
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2024 The Author(s). Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.
See related article on page 476 and 480.
A full list of RIETE investigators is given in Appendix S1.
Supervising Editor: Alice M. Mitchell
1Department of Emergency Medicine,
Lausanne University Hospital, Lausanne,
Switzerland
2Department of Angiology, Lausanne
University Hospital, Lausanne,
Switzerland
3Department of Internal Medicine, Hospital
Universitario La Paz, Madrid, Spain
4Department of Internal Medicine,
Hospital Universitario Virgen de Arrixaca,
Murcia, Spain
5PHI University Clinic of Pulmology and
Allergy Skopje, Skopje, Republic of North
Macedonia
6 Department of Pneumonology, Hospital
Universitario Donostia, San Sebastián,
Guipúzcoa, Spain
7 Department of Internal Medicine,
Hospital de la Axarquía, Málaga, Spain
8 Department of Internal Medicine and
Emergency Room, Presidio Ospedaliero S.
Maria Delle Grazie, Naples, Italy
9Faculty of Health Sciences, Universidad
Católica San Antonio de Murcia (UCAM),
Murcia, Spain
10CIBER Enfermedades Respiratorias
(CIBERES), Madrid, Spain
Correspondence
Prof Olivier Hugli, Emergency
Department, Lausanne University
Hospital, BH 09-777, Bugnon 46, 1011
Lausanne, Switzerland.
Email: olivier.hugli@chuv.ch
Abstract
Background: The use of a computed tomography pulmonary angiogram to diagnose
pulmonary embolism (PE) has increased, leading not only to higher PE diagnoses but
also to overdiagnosis and unnecessary radiation exposure, even in young patients de-
spite a lower PE incidence. The aim of this study was to assess the failure rate of the
pulmonary embolism rule-out criteria 35 (PERC-35) rule developed to reduce unnec-
essary testing in individuals aged ≤35 years among patients included in the Registro
Informatizado de la Enfermedad TromboEmbolica Venosa (RIETE) Registry.
Methods: This retrospective cohort study used data from the RIETE Registry, an on-
going, international prospective registry of patients with objectively confirmed ve-
nous thromboembolism. The primary outcome was the missed PE rate using PERC-35
criteria. Secondary outcomes included the comparison of demographic and clinical
characteristics, PE localization, treatment strategies, and outcomes between PERC-
negative (PERC-35N) versus PERC-positive (PERC-35P) patients.
Results: Of 58,918 adult patients with acute PE, the PERC-35 rule demonstrated a
low missed PE rate of 0.35% (n = 204), with an upper 95% confidence interval [CI]
of 0.40%. The missed rate was 7.0% (95% CI 6.0%–7.9%) in the 18- to 35-year sub-
group. Compared to PERC-35P patients, PERC-35N patients were younger (mean age
28.4 years), with a lower body mass index, and included a higher proportion of preg-
nant/postpartum women. PERC-35N patients had a significantly lower rate of chronic
diseases and presented less frequently with dyspnea or syncope but more often with
chest pain. They showed lower rates of positive D-dimer and troponin levels. PERC-
35N patients experienced fewer major bleeding episodes, similar recurrence rates of
PE/deep vein thrombosis, and no deaths during anticoagulation.
| 415JOSSEIN et al.
I NTRO D U C TI O N
Pulmonary embolism (PE) is a significant concern in the emergency
department (ED) and associated with high mortality if untreated.
Although PE mortality is higher in older patients, it also significantly
affects younger patients, particularly young women. 1,2 Studies show
that in nearly 400,000 autopsy cases, critical PE was found in 2.3%
of the 20- to 39-year age group. The combination of nonspecific
PE presentation, a poor outcome of missed PE, and the widespread
availability of computed tomography pulmonary angiogram (CTPA)
in most EDs has led to an increased imaging rate.3 Consequently,
more PEs are diagnosed, especially subsegmental PEs whose clinical
significance remains a subject of debate.4 However, this rise in CTPA
use leads to prolonged ED stays,5 increased radiation exposure, and
higher health care costs.
To address the potential overuse of CTPA and the subsequent
overdiagnosis of PE, particularly in younger patients, a clinical deci-
sion rule, the pulmonary embolism rule-out criteria (PERC) rule has
been developed to help rule out PE without additional testing in pa-
tients <50 years with a low PE pretest probability by clinical gestalt
or Wells score. 6 This approach avoids unnecessary D- dimer test-
ing and pulmonary imaging. Our recent study using data from the
Registro Informatizado de la Enfermedad Tromboembólica (RIETE)
Registry demonstrated that the PERC rule had a low missed PE rate
of 0.7%.7
Age is a crucial risk factor for PE, with an incidence 10 times
lower in adults aged 18–35 years than in those over 65 years. 8
Despite these differences, CTPA rates are similar between younger
and older patients, resulting in a diagnostic yield 5.6 and 7.6 times
lower in younger male and female patients, respectively.9 According
to a recent study in the United States, 21% of CTPAs were per-
formed on women under 45 years.10 Young women are at higher risk
of overtesting due to their greater lifetime risk of radiation-induced
breast cancer, estimated at 0.4% for 20-year-old female patients.11
Given the lower PE prevalence and increased radiation risk in
young patients,12 the PERC-35 rule, a modification of the original
PERC rule,9 was specifically developed for patients aged 35 years
and younger (Appendix S2). This modification of the original PERC
rule substitutes fever for heart rate as tachycardia failed to meet
the thresholds required by the creators of the rule to be retained
as a final PE predictor in the 18- to 35-year age group. On the other
hand, fever was a significant predictor in this younger age group,
thus justifying the switch.9 In the PRINCEPS study, applying the
PERC-35 rule to the 1839 patients aged 18–35 years in the PERC
data set would have reduced testing by 62% and increased the PE
diagnostic yield from 4.0% to 9.2%.9 Moreover, a recent retrospec-
tive study using three European cohorts totaling 1235 patients aged
18–35 years found the PERC-35 failure rate to be 0.9%, similar to the
PERC rule.13 However, the 95% confidence interval (CI) was above
2%, higher than the threshold of 1.85% considered as the maximal
false-negative rate to safely exclude a PE in the ED.14 This encour-
aging low failure rate of the PERC-35 rule suggested that it could
be a valuable tool if validated externally as both accurate and safe.
Therefore, the main goal of this study was to assess the missed PE
rate of the PERC-35 rule in a larger cohort of PE adult patients en-
rolled in the RIETE Registry.
M E TH O DS
Study design
This retrospective cohort study is based on data of patients ≥18 years
included in the RIETE Registry from its initiation on March 1, 2001,
through July 30, 2023. The methodology of the RIETE Registry has
been described previously.15 Briefly, this ongoing international pro -
spective registry has enrolled consecutive patients of any age with
objectively confirmed venous thromboembolism (VTE) since 2001. At
each participating site, local investigators enroll consecutive patients.
Auditors regularly check for the sequential inclusion of patients, data
completeness, and accuracy. Exclusion criteria include participation in
another clinical trial involving the blinding of a patient's medication
or unavailability for a 3-month follow-up. The ethics committees at
all participating sites approved the protocol for enrollment and all
patients or their health care proxies provided informed consent. As
of October 2023, over 101,000 patients had been included and fol-
lowed-up for at least 3 months in 210 hospitals from 26 countries.
Measures
The primary outcome of our study was the overall percentage of
PE patients included in the RIETE registry with all eight negative
PERC-35 criteria (PERC- 35N), representing the missed PE rate of
the rule. Secondary outcomes included: (1) identifying specific
characteristics associated with PERC- 35N patients; (2) comparing
Conclusions: The PERC-35 rule demonstrated a low failure rate to exclude PE in pa-
tients aged 18–35 years and could reduce imaging and radiation exposure in young
patients with a low PE pretest probability if confirmed prospectively.
K E Y W O R D S
diagnostic algorithm, PERC, pretest probability, pulmonary embolism, pulmonary embolism
rule-out criteria rule, RIETE
I NTRO D U C TI O N
Pulmonary embolism (PE) is a significant concern in the emergency
department (ED) and associated with high mortality if untreated.
Although PE mortality is higher in older patients, it also significantly
affects younger patients, particularly young women. 1,2 Studies show
that in nearly 400,000 autopsy cases, critical PE was found in 2.3%
of the 20- to 39-year age group. The combination of nonspecific
PE presentation, a poor outcome of missed PE, and the widespread
availability of computed tomography pulmonary angiogram (CTPA)
in most EDs has led to an increased imaging rate.3 Consequently,
more PEs are diagnosed, especially subsegmental PEs whose clinical
significance remains a subject of debate.4 However, this rise in CTPA
use leads to prolonged ED stays,5 increased radiation exposure, and
higher health care costs.
To address the potential overuse of CTPA and the subsequent
overdiagnosis of PE, particularly in younger patients, a clinical deci-
sion rule, the pulmonary embolism rule-out criteria (PERC) rule has
been developed to help rule out PE without additional testing in pa-
tients <50 years with a low PE pretest probability by clinical gestalt
or Wells score. 6 This approach avoids unnecessary D- dimer test-
ing and pulmonary imaging. Our recent study using data from the
Registro Informatizado de la Enfermedad Tromboembólica (RIETE)
Registry demonstrated that the PERC rule had a low missed PE rate
of 0.7%.7
Age is a crucial risk factor for PE, with an incidence 10 times
lower in adults aged 18–35 years than in those over 65 years. 8
Despite these differences, CTPA rates are similar between younger
and older patients, resulting in a diagnostic yield 5.6 and 7.6 times
lower in younger male and female patients, respectively.9 According
to a recent study in the United States, 21% of CTPAs were per-
formed on women under 45 years.10 Young women are at higher risk
of overtesting due to their greater lifetime risk of radiation-induced
breast cancer, estimated at 0.4% for 20-year-old female patients.11
Given the lower PE prevalence and increased radiation risk in
young patients,12 the PERC-35 rule, a modification of the original
PERC rule,9 was specifically developed for patients aged 35 years
and younger (Appendix S2). This modification of the original PERC
rule substitutes fever for heart rate as tachycardia failed to meet
the thresholds required by the creators of the rule to be retained
as a final PE predictor in the 18- to 35-year age group. On the other
hand, fever was a significant predictor in this younger age group,
thus justifying the switch.9 In the PRINCEPS study, applying the
PERC-35 rule to the 1839 patients aged 18–35 years in the PERC
data set would have reduced testing by 62% and increased the PE
diagnostic yield from 4.0% to 9.2%.9 Moreover, a recent retrospec-
tive study using three European cohorts totaling 1235 patients aged
18–35 years found the PERC-35 failure rate to be 0.9%, similar to the
PERC rule.13 However, the 95% confidence interval (CI) was above
2%, higher than the threshold of 1.85% considered as the maximal
false-negative rate to safely exclude a PE in the ED.14 This encour-
aging low failure rate of the PERC-35 rule suggested that it could
be a valuable tool if validated externally as both accurate and safe.
Therefore, the main goal of this study was to assess the missed PE
rate of the PERC-35 rule in a larger cohort of PE adult patients en-
rolled in the RIETE Registry.
M E TH O DS
Study design
This retrospective cohort study is based on data of patients ≥18 years
included in the RIETE Registry from its initiation on March 1, 2001,
through July 30, 2023. The methodology of the RIETE Registry has
been described previously.15 Briefly, this ongoing international pro -
spective registry has enrolled consecutive patients of any age with
objectively confirmed venous thromboembolism (VTE) since 2001. At
each participating site, local investigators enroll consecutive patients.
Auditors regularly check for the sequential inclusion of patients, data
completeness, and accuracy. Exclusion criteria include participation in
another clinical trial involving the blinding of a patient's medication
or unavailability for a 3-month follow-up. The ethics committees at
all participating sites approved the protocol for enrollment and all
patients or their health care proxies provided informed consent. As
of October 2023, over 101,000 patients had been included and fol-
lowed-up for at least 3 months in 210 hospitals from 26 countries.
Measures
The primary outcome of our study was the overall percentage of
PE patients included in the RIETE registry with all eight negative
PERC-35 criteria (PERC- 35N), representing the missed PE rate of
the rule. Secondary outcomes included: (1) identifying specific
characteristics associated with PERC- 35N patients; (2) comparing
Conclusions: The PERC-35 rule demonstrated a low failure rate to exclude PE in pa-
tients aged 18–35 years and could reduce imaging and radiation exposure in young
patients with a low PE pretest probability if confirmed prospectively.
K E Y W O R D S
diagnostic algorithm, PERC, pretest probability, pulmonary embolism, pulmonary embolism
rule-out criteria rule, RIETE