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Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing

Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary... Research JAMA Cardiology | Original Investigation Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Pierre-Marie Roy, MD, PhD; Emilie Friou, MD; Boris Germeau, MD; Delphine Douillet, MD; Jeffrey Allen Kline, MD, PhD; Marc Righini, MD, PhD; Grégoire Le Gal, MD, PhD; Thomas Moumneh, MD; Andrea Penaloza, MD, PhD Supplemental content IMPORTANCE In patients with suspected pulmonary embolism (PE), overuse of diagnostic imaging is an important point of concern. OBJECTIVE To derive and validate a 4-level pretest probability rule (4-Level Pulmonary Embolism Clinical Probability Score [4PEPS]) that makes it possible to rule out PE solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing for suspected PE. DESIGN, SETTING, AND PARTICIPANTS This study included consecutive outpatients suspected of having PE from US and European emergency departments. Individual data from 3 merged management studies (n = 11 114; overall prevalence of PE, 11%) were used for the derivation cohort and internal validation cohort. The external validation cohorts were taken from 2 independent studies, the first with a high PE prevalence (n = 1548; prevalence, 21.5%) and the second with a moderate PE prevalence (n = 1669; prevalence, 11.7%). A prior definition of pretest probability target values to achieve a posttest probability less than 2% was used on the basis of the negative likelihood ratios of D-dimer. Data were collected from January 2003 to April 2016, and data were analyzed from June 2018 to August 2019. MAIN OUTCOMES AND MEASURES The rate of PE diagnosed during the initial workup or during follow-up and the rate of imaging testing. RESULTS Of the 5588 patients in the derivation cohort, 3441 (61.8%) were female, and the mean (SD) age was 52 (18.5) years. The 4PEPS comprises 13 clinical variables scored from −2 to 5. It results in the following strategy: (1) very low probability of PE if 4PEPS is less than 0: PE ruled out without testing; (2) low probability of PE if 4PEPS is 0 to 5: PE ruled out if D-dimer level is less than 1.0 μg/mL; (3) moderate probability of PE if 4PEPS is 6 to 12: PE ruled out if D-dimer level is less than the age-adjusted cutoff value; (4) high probability of PE if 4PEPS is greater than 12: PE ruled out by imaging without preceding D-dimer test. In the first and the second external validation cohorts, the area under the receiver operator characteristic curves were 0.79 (95% CI, 0.76 to 0.82) and 0.78 (95% CI, 0.74 to 0.81), respectively. The false-negative testing rates if the 4PEPS strategy had been applied were 0.71% (95% CI, 0.37 to 1.23) and 0.89% (95% CI, 0.53 to 1.49), respectively. The absolute reductions in imaging testing were −22% (95% CI, −26 to −19) and −19% (95% CI, −22 to −16) in the first and second external validation cohorts, respectively. The 4PEPS strategy compared favorably with all recent strategies in terms of imaging testing. CONCLUSIONS AND RELEVANCE The 4PEPS strategy may lead to a substantial and safe reduction in imaging testing for patients with suspected PE. It should now be tested in a formal outcome study. Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Pierre-Marie Roy, MD, PhD, Emergency Department, CHU Angers, Institut Mitovasc UMR (CNRS 6015—INSERM 1083), UNIV Angers, F-CRIN INNOVTE, 4 Rue Larrey, 49933 JAMA Cardiol. 2021;6(6):669-677. doi:10.1001/jamacardio.2021.0064 Angers, France (pmroy@ Published online March 3, 2021. chu-angers.fr). (Reprinted) 669 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing espite the significant progress of the last decades, di- agnosing pulmonary embolism (PE) remains a clini- Key Points D cal challenge. The standard diagnostic strategy, based Question Can a pretest probability score make it possible to rule on clinical probability assessment, D-dimer testing, and com- out pulmonary embolism solely on clinical criteria and optimized puted tomography pulmonary angiography (CTPA), is proven D-dimer measurement to safely decrease imaging testing? to have a very low rate of diagnostic failure. However, there Findings In this study, the 4-Level Pulmonary Embolism Clinical 2,3 has been a large increase in CTPA for suspected PE. The ex- Probability Score (4PEPS) was derived and validated using act reasons are likely multifactorial. The signs and symptoms databases from 3 merged management studies. The safety and the of PE are very common and unspecific. As such, clinicians fear efficacy of the 4PEPS strategy was confirmed in 2 external they might be missing a life-threatening condition and are validation cohorts (false-negative rates: 0.71% and 0.89%; absolute reductions in imaging testing: −19% and −22%, prone to initiate a diagnostic process. Due to the lack of speci- respectively). ficity of D-dimer testing, a large proportion of patients have a false-positive result and require imaging to rule out PE. Fi- Meaning The 4PEPS strategy may lead to a substantial and safe nally, CTPA is readily available, fast, minimally invasive, and reduction in imaging testing for patients with suspected pulmonary embolism. more sensitive than ventilation/perfusion (V/Q) scans. A slight increase in PE diagnosis has been observed as a result but with no clear benefits in terms of outcome, especially PE-related established using the results of the YEARS study and the Age- 4,5 mortality. One explanation is that because more CTPAs are Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Em- being performed, there is a greater risk of false-positive re- bolism (ADJUST-PE) study. They were found to be 0.08 and sults or non–clinically relevant diagnoses. Moreover, CTPA ex- 0.01, respectively. Accordingly, to achieve a posttest probabil- poses patients to risks of allergies, kidney failure, and cumu- ity less than 2%, the upper limit of PE prevalence was set at 6,7 lative radiation-induced cancer. Several strategies have 20% for low CPP and at 65% for moderate CPP. The present therefore been proposed to reduce PE overtesting and over- study was a retrospective analysis of data prospectively col- 4,8-14 diagnosis(Table 1). Thesehaveprovedsatisfactoryinterms lected in 5 studies that were all approved by an ethical com- of safety and efficacy, but they are based on different meth- mittee and performed with the informed consent of the par- ods of assessing clinical pretest probability (CPP; eg, Wells or ticipating patients. According to the current European revised Geneva scores for PE, Pulmonary Embolism Rule- legislation, an approval of an ethical committee was not re- 10 12 out Criteria [PERC] strategy, or YEARS strategy ), thus mak- quired for the present study. ing it difficult to combine them and increasing the risk of mis- use in clinical practice. Source of Data Our primary aim was to develop and validate a pretest For the derivation and internal validation, we merged 3 pro- probability score to safely reduce imaging testing by integrat- spectively collected databases from patients with suspected ing all the previously proposed strategies: the 4-Level Pulmo- PE (n = 11 114). The first study was performed in 117 emer- nary Embolism Clinical Probability Score (4PEPS). Our sec- gency departments (EDs) in France and Belgium (n = 1529; en- ondary goal was to retrospectively assess the safety of a rolled in 2003) ; the second study was performed in 20 French diagnostic strategy based on this new score and its efficacy in EDs (n = 1645; enrolled in 2005 to 2006) ; and the third study reducing imaging testing. was performed in 12 EDs in the US (n = 7940; enrolled in 2003 to 2006). Each database was randomly split into 2 groups, including 60% for the derivation cohort and 40% for the in- ternal validation cohort. Methods Two other databases were used for external validation. The Study Design first study was performed in 6 EDs in France, Belgium, and Four levels of CPP for 4PEPS were defined a priori: Switzerland (n = 1819; enrolled in 2005 to 2006) and the sec- • Very low CPP, allowing exclusion of PE on clinical criteria only. ond in 12 EDs in France and Belgium (n = 1757; enrolled in 2015 • Low CPP, allowing exclusion of PE with a high-sensitivity to 2016). D-dimer level less than 1.0 μg/mL (to convert to nanomoles per liter, multiply by 5.476). Outcome • Moderate CPP, allowing exclusion of PE with a D-dimer level The outcome was a PE diagnosed on CTPA or high- less than 0.5 μg/mL or less than the age-adjusted cutoff value probability V/Q scan during the initial diagnostic workup or a (calculated as age × 0.01 μg/mL for patients older than venous thromboembolism (VTE) occurring during follow-up 50 years). (3 months for the 4 European studies and 45 days for the US • High CPP, not allowing a safe exclusion of PE with D-dimer study) in a patient in whom PE was initially ruled out. In all testing and requiring imaging testing (CTPA or V/Q scan). studies, the following were considered as VTE: symptomatic To derive the score, we predefined the upper limit for PE PE objectively confirmed with CTPA or high-probability V/Q prevalence in each CPP category using the bayesian approach scan and/or deep vein thrombosis on compression ultraso- 13,15,16 and considered 2% as the safety threshold for PE. The nography and/or sudden unexpected death potentially negative likelihood ratios of a D-dimer test using 1.0 μg/mL as related to PE according to an independent adjudication the cutoff value and using an age-adjusted cutoff value were committee. 670 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research Table 1. Diagnostic Strategy Aiming to Reduce Imaging Testing PE strategy No diagnostic test required D-dimer test required D-dimer cutoff value CTPA or V/Q scan required Standard NA Nonhigh CPP with RG score (0-10), <0.5 μg/mL High CPP or positive D-dimer a,b Wells score (0-4), or gestalt test result PERC strategy Low CPP with gestalt and Low CPP and positive PERC score (>0) <0.5 μg/mL High CPP or positive D-dimer negative PERC score (0) or intermediate CPP with gestalt test result a d ADJUST-PE NA Nonhigh CPP with RG score (0-10) Age adjusted High CPP or positive D-dimer d a strategy or Wells score (0-4) test result e e YEARS strategy NA YEARS score negative (0) <1.0 μg/mL Positive D-dimer test result YEARS score positive (>0) <0.5 μg/mL f b PEGeD strategy NA Low CPP with Wells score (0-4) <1.0 μg/mL High CPP or positive D-dimer test result Moderate CPP with Wells score (4.5-6) <0.5 μg/mL 4PEPS Very low CPP with 4PEPS (<0) Low CPP with 4PEPS (0-5) <1.0 μg/mL High CPP with 4PEPS (>12) or positive D-dimer test result Moderate CPP 4PEPS (6-12) Age adjusted Abbreviations: 4PEPS, 4-Level Pulmonary Embolism Clinical Probability Score; beats per minute (+1.5), clinical signs of deep venous thrombosis (+3), PE is the ADJUST-PE, Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary most likely diagnosis (+3). Embolism; CPP, clinical pretest probability; CTPA, computed tomography PERC strategy: age of 50 years or older (+1), heart rate of 100 beats per minute pulmonary angiography; PE, pulmonary embolism; PEGeD, Pulmonary or greater (+1), room air pulse oximetry less than 95% (+1), unilateral leg Embolism Graduated d-Dimer; PERC, Pulmonary Embolism Rule-out Criteria; edema (+1), hemoptysis (+1), recent surgery or trauma in the past 4 weeks RG, revised Geneva; V/Q, ventilation/perfusion. 10 (+1). SI conversion factor: To convert D-dimer to nanomoles per liter, multiply d ADJUST-PE strategy study: age-adjusted D-dimer cutoff value less than 0.5 by 5.476. μg/mL for patients younger than 50 years and calculated as age × 0.01 μg/mL a 11 RG score: age of 65 years or older (+1), previous deep venous thrombosis or PE for patients 50 years or older. (+3), surgery or lower limb fracture in the past month (+2), active cancer (+2), e YEARS strategy: 3-factor clinical rule derived from revised Wells score for PE, unilateral lower limb pain (+3), hemoptysis (+2), heart rate of 75 to 94 beats including clinical signs of deep vein thrombosis (+1), hemoptysis (+1), and PE is per minute (+3) or 95 beats per minute or greater (+5), pain on lower limb 12 the most likely diagnosis (+1). deep venous palpation and unilateral edema (+4). f 13 PEGeD strategy: strategy using the 3-level revised Wells score for PE. Wells score (revised Wells score for PE): active cancer (+1), surgery or Age-adjusted cutoff value less than 0.5 μg/mL for patients younger than 50 bedridden for 3 or more days during the past 4 weeks (+1.5), previous deep years and calculated as age × 0.01 μg/mL for patients 50 years or older. venous thrombosis or PE (+1.5), hemoptysis (+1), heart rate greater than 100 We performed a stepwise backward analysis including 1 4PEPS Derivation 23,24 We evaluated all of the clinical variables known to be poten- variable for every 10 VTE events. We then removed the tially associated with PE and available in the database. As pa- nonsignificant variables, considering a 2-tailed P value less tients were suspected of PE because of dyspnea or chest pain, than .05 as significant. Only significant variables were left in these variables were not included. However, we took the vari- the final score. We assigned points for the score according to able of dyspnea and chest pain into account when both were the regression coefficients. Finally, we chose the cutoff val- present in a given patient. Variables with more than 2% of miss- ues to achieve the predefined levels of PE prevalence in ing data were excluded, except those included in other pre- each CPP category. 10 8 diction rules (PERC strategy, revised Geneva score, and Wells score ). Namely, the following variables were excluded: his- 4PEPS Validation tory of hypertension, diabetes, dyslipidemia, coronary dis- The accuracy of the score was assessed by calculating the re- ease, long travel, chronic kidney failure, smoking, family his- ceiver operating characteristic curve and analyzing the area un- tory of VTE, body weight, respiratory rate, and antiplatelet der the receiver operating characteristic curve (AUC). The AUC treatment. We categorized the continuous variables accord- confidence interval was computed with the DeLong-DeLong ing to the cutoff values previously chosen in other scoring sys- method. Calibration was assessed with the Hosmer- tems and according to their clinical relevance. There were 4 Lemeshow goodness-of-fit statistic. A Brier score was also categories for age (younger than 50 years, aged 50 to 64 years, reported, summarizing the magnitude of error in the probabil- aged 65 to 80 years, and older than 80 years), 3 categories for ity forecasts as between 0.0 and 1.0, where a perfectly cali- heart rate (less than 80 beats per minute, 80 to 100 beats per brated model would score 0.0. minute, and more than 100 beats per minute) and tempera- ture (less than 38 °C, 38 to 39 °C, and greater than 39 °C), and 4PEPS Strategy Safety and Efficacy Assessment 2 categories for systolic blood pressure (less than 90 mm Hg The safety of the 4PEPS strategy was retrospectively as- and 90 mm Hg or greater) and pulse oximetry (Spo ; less than sessed using the false-negative rate if the strategy had been 95% and 95% or greater). applied in the 2 external validation cohorts. This is the rate of To select the predictor variables associated with PE, we PE diagnoses during the initial diagnostic process or VTEs 2 22 performed a univariate analysis by using the χ test. All found during the 3-month follow-up among patients with a variables with a 2-tailed P value less than .20 as well as the very low CPP, a low CPP and D-dimer level less than 1.0 μg/ nonsignificant variables included in other prediction rules mL, a moderate CPP and D-dimer level less than the age- were included in a multivariate logistic regression model. adjusted cutoff value, or a negative CTPA or V/Q scan. jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 671 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Table 2. Baseline Characteristics of the Patients in the Different Cohorts Cohort, No. (%) External validation Internal Moderate Derivation validation High prevalence prevalence Characteristic (n = 5588) (n = 3726) (n = 1548) (n = 1669) Demographic characteristics Age, mean (SD), y 52 (18.5) 52 (18.5) 59 (18.7) 53 (19.8) Male 2147 (38.4) 1461 (39.2) 706 (45.6) 699 (41.9) Treatment and medical history Hormonal estrogenic treatment 417 (7.5) 272 (7.3) 132 (8.5) 189 (11.3) History of VTE 705 (12.6) 486 (13.0) 266 (17.2) 199 (11.9) Current malignancy 688 (12.3) 403 (10.8) 114 (7.4) 133 (8.0) Chronic respiratory disease 1121 (20.1) 724 (19.4) 193 (12.5) 139 (8.3) Chronic heart failure 532 (9.5) 330 (8.9) 82 (5.3) 94 (5.6) Immobility within 4 wk 819 (14.7) 523 (14.0) 225 (14.6) 200 (12.0) Pregnancy 83 (1.5) 61 (1.6) 0 15 (0.9) Postpartum within 4 wk 84 (1.5) 48 (1.3) 12 (0.8) 9 (0.5) Symptoms Chest pain 3572 (63.9) 2363 (63.4) 1070 (69.1) 1103 (66.1) Dyspnea 3809 (68.2) 2545 (68.3) 1108 (71.6) 927 (55.5) Abbreviations: DVT, deep vein thrombosis; PE, pulmonary Chest pain and dyspnea 2323 (41.6) 1570 (42.1) 704 (45.5) 479 (28.7) embolism; VTE, venous Syncope 496 (8.9) 328 (8.8) 321 (20.7) 315 (18.9) thromboembolism. Clinically suspected DVT 620 (11.1) 403 (10.8) 270 (17.4) 242 (14.5) Cancer or treatment for cancer within 1 year. Hemoptysis 187 (3.4) 123 (3.3) 71 (4.6) 47 (2.8) Surgery, lower limb plaster cast, or Signs, mean (SD) bedridden more than 3 days for Heart rate, beats per minute 92 (21.3) 92 (20.8) 8.7 (19.8) 87 (19.5) acute medical condition within the last 4 weeks. Systolic blood pressure, mm Hg 133 (24.6) 133 (24.9) 139 (22.4) 136 (21.2) Unilateral lower limb spontaneous Room air pulse oximetry, % 96 (4.7) 96 (4.4) 95 (5.0) 96 (3.7) pain, pain on deep vein palpation, or Temperature, °C 36.8 (0.7) 36.8 (0.7) 37.1 (1.3) 36.8 (0.7) swelling. PE is the most likely diagnosis 1169 (20.9) 774 (20.7) 718 (46.4) 348 (20.9) PE diagnosed during the initial diagnostic workup or symptomatic Final PE prevalence 615 (11.0) 432 (11.6) 332 (21.5) 196 (11.7) VTE occurred during the follow-up. We defined the safety threshold of the 4PEPS strategy as ables of 4PEPS as negative, ie, resulting in the lowest score and a function of PE prevalence applying the recommendations of so representing the highest risk of a false-negative finding using the International Society of Thrombosis and Hemostasis the 4PEPS strategy. (1.82 + [0.00528 × prevalence]). The respective PE preva- lences in the first and second external validation cohorts were Statistical Analysis 21.4% and 11.7%, respectively. Thus, the acceptable upper lim- We calculated the 95% CIs by using the Mid-P exact value per- itsofthe95%CIoffalse-negativerateswerepredefinedat1.93% formed using OpenEpi version 2, an open-source calculator. and 1.88%, respectively. All other statistical analyses were performed using SPSS ver- Finally, the efficacy of the 4PEPS strategy was assessed by sion 25.0 (SPSS Inc). the rate of D-dimer and imaging testing, mainly CTPA, that could have been avoided if the 4PEPS strategy had been ap- plied compared with the standard strategy, the PERC strategy, Results 11 12 the ADJUST-PE strategy, the YEARS strategy, and the Pul- monary Embolism Graduated D-Dimer (PEGeD) strategy After exclusion of patients with missing data, 5588 patients (Table 1). were included in the derivation cohort (PE prevalence, 11.0%), 3726 in the internal validation cohort (PE prevalence, 11.7%), 1548 in the first external validation cohort (PE prevalence, 21.5), Missing Data Analyses were performed including all analyzable patients. Pa- and 1669 in the second external validation cohort (PE preva- tients with missing data were excluded and no imputation was lence, 11.7%). Of the 5588 patients in the derivation cohort, 3441 performed. However, a sensitivity analysis was carried out for (61.8%) were female, and the mean (SD) age was 52 (18.5) years. the 2 external validation cohorts considering the missing vari- In the 3 validation cohorts, 2265 of 3726 (60.7%), 842 of 1548 672 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research (54.4%), and 970 of 1669 (58.1%) were female, and the mean Table 3. 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) (SD) age was 52 (18.5), 59 (18.7), and 53 (19.8) years, respec- Regression tively. Characteristics of the study samples are presented in Variable coefficient Points Table 2. Age, y <50 −0.993 −2 4PEPS Derivation 50-64 −0.656 −1 A univariate analysis found a statistical association with PE di- Chronic respiratory disease −0.570 −1 agnosis for 21 variables. All of these were included in the mul- Heart rate <80 beats per minute −0.406 −1 tivariate regression. In addition, we included the variable of Chest pain and acute dyspnea 0.297 1 estrogenic treatment since this criterion is present in the PERC Male 0.472 2 strategy. In the multivariate model, age of 65 to 80 years or Hormonal estrogenic treatment 0.608 2 older than 80 years, pulse rate of 80 to 100 beats per minute, Personal history of VTE 0.711 2 systolic arterial pressure, hemoptysis, cancer, chronic car- Syncope 0.504 2 diac failure, and pregnancy or post partum were not indepen- Immobility within the last 4 wk 0.509 2 dently associated with PE. The remaining 13 variables were in- Pulse oxygen saturation <95% 0.832 3 cluded in the final model, and we assigned points for each of Calf pain and/or unilateral lower limb edema 1.009 3 them according to their regression coefficient. Table 3 repre- PE is the most likely diagnosis 1.860 5 sents the final model (4PEPS). Clinical probability, total The PE prevalence by 4PEPS and the distribution of 4PEPS Very low CPP (<2%): PE can be ruled out <0 in the derivation cohort are presented in the Figure and the eTable in the Supplement. According to the predefined cutoff Low CPP (2%-20%): PE can be ruled 0-5 out if D-dimer level <1.0 μg/mL values, a 4PEPS less than 0 corresponds to a very low CPP (less Moderate CPP (20%-65%): PE can be 6-12 than 2%), a 4PEPS of 0 to 5 corresponds to a low CPP (less than ruled out if D-dimer level <0.5 μg/mL or <(age × 0.01) μg/mL 20%), a 4PEPS of 6 to 12 corresponds to a moderate CPP (less High CPP (>65%): PE cannot be ruled out ≥13 than 65%), and a 4PEPS greater than 12 corresponds to a high without imaging testing CPP (65% or greater) (Table 3). PE prevalence in the very low Abbreviations: CPP, clinical pretest probability; PE, pulmonary embolism; VTE, category was 1.1% (95% CI, 0.6-1.6); low category, 6.2% (95% venous thromboembolism. CI, 5.3-7.1); intermediate category, 31.3% (95% CI, 28.6-34.1); SI conversion factor: To convert D-dimer to nanomoles per liter, multiply by and high category, 73.6% (95% CI, 65.2-82.0). 5.476. Surgery, lower limb plaster cast, or bedridden more than 3 days for acute medical condition within the last 4 weeks. 4PEPS Validation For the 3 validation cohorts, the PE prevalence by 4PEPS and the distribution of the 4PEPS are presented in the Figure and Compared with the standard strategy (CPP assessed using the eTable in the Supplement. In the internal validation co- the revised Geneva score, D-dimer measurement with 0.5 hort, the AUC was 0.83 (95% CI, 0.81-0.85). In the first and sec- μg/mL as the cutoff value), applying 4PEPS would have de- ond external validation cohort, the AUCs were 0.79 (95% CI, creased the CTPA rate (external validation cohort 1: 46% vs 0.76-0.82) and 0.78 (95% CI, 0.74-0.81), respectively. The AUCs 68%; difference, −22%; 95% CI, −26 to −19; external valida- and the degree of concordance between the observed and tion cohort 2: 32% vs 51%; difference, −19%; 95% CI, −22 to −16). 10-13 predicted prevalence are presented in the eFigure in the Table 4 compares the different strategies proposed to re- Supplement. duce diagnostic testing. 4PEPS Strategy Validation When the 4PEPS strategy was retrospectively applied in the Discussion first and second external validation cohorts, the false- negative rates were 11 of 1548 (0.71%; 95% CI, 0.37-1.23) and Using 5 multicenter cohorts regrouping more than 12 000 pa- 14 of 1570 (0.89%; 95% CI, 0.53-1.49), respectively. No fatal PE tients suspected of PE, we were able to derive and validate a or high-risk hemodynamically unstable PE were observed, and new clinical probability score to help physicians diagnose PE 3 of 11 false-negative VTEs in the high-prevalence cohort and and safely decrease diagnostic imaging. Applying the 4PEPS 3 of 14 false-negative VTEs in the moderate-prevalence co- diagnostic strategy retrospectively to 2 external validation co- hort were subsegmental PE. The upper limit of the 95% CI of horts, the rate of false-negative tests was below 1%, and the the false-negative rate was less than the predefined cutoff value 4PEPS strategy performed better than all previously pro- to consider the 4PEPS strategy as safe in the first (1.93%) and posed strategies in terms of reducing imaging testing. second (1.88%) external validation cohorts. Similar results were Overuse of CTPA for suspected PE is an important concern. observed in the sensitivity analyses considering missing vari- There is increasing evidence that CTPA is frequently used in- ables of 4PEPS as negative (high-prevalence cohort: 11 of 1687; appropriately in patients for whom the benefits (probability false-negative rate, 0.65%; 95% CI, 0.34-1.13; moderate- of PE diagnosis and avoiding a PE complication) are out- prevalence cohort: 14 of 1655; false-negative rate, 0.85%; 95% weighed by the risks (probability of a false-positive result, com- CI, 0.50-1.61). plication of anticoagulation, short-term or long-term adverse jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 673 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Figure. Pulmonary Embolism Prevalence by 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) in the Derivation and Validation Cohorts Derivation cohort Internal validation cohort External validation cohort 1 External validation cohort 2 ≤–3 –2 –1 0 123456789 10 11 12 13 14 ≥15 4-Level Pulmonary Embolism Clinical Probability Score Table 4. Diagnostic Tests and False-Negative Testing According to the Strategy Retrospectively Applied External validation cohort, No. (%) High prevalence (n = 1546) Moderate prevalence (n = 1555) Strategy D-dimer test CTPA or V/Q scan False-negatives D-dimer test CTPA or V/Q scan False-negatives Standard 1474 (95.3) 1058 (68.4) 4 (0.2) 1517 (97.6) 795 (51.1) 0 PERC strategy 1188 (76.7) 981 (63.4) 16 (1.0) 1143 (73.5) 758 (48.7) 4 (0.3) ADJUST-PE strategy 1474 (95.3) 890 (57.6) 5 (0.3) 1517 (97.6) 714 (45.9) 0 YEARS strategy 1546 (100) 885 (58.2) 11 (0.7) 1555 (100) 582 (37.4) 9 (0.6) PEGeD strategy 1429 (92.4) 817 (52.9) 12 (0.8) 1485 (95.5) 553 (35.6) 11 (0.7) 4PEPS 1341 (86.7) 713 (46.1) 11 (0.7) 1198 (77.0) 499 (32.1) 14 (0.9) Abbreviations: 4PEPS, 4-Level Pulmonary Embolism Clinical Probability Score; Pulmonary Embolism Graduated d-Dimer; PERC, Pulmonary Embolism Rule-out ADJUST-PE, Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Criteria; V/Q, ventilation/perfusion. Embolism; CTPA, computed tomography pulmonary angiography; PEGeD, 2,3,27 effect of CTPA). The first strategy developed to deal with the ADJUST-PE strategy on imaging testing rates remains lim- 10,15 overtesting was the PERC strategy. This can be used for pa- ited (−10.8% or −5.2% in our high-prevalence and moderate- tients for whom the clinician has already established alow clini- prevalence external validation cohorts, respectively), particu- cal probability of PE based on an implicit gestalt impression. larly in young patients. A further proposal, based on the Bayes A negative PERC strategy finding defines a subgroup of these theorem, is to adjust the D-dimer cutoff value to the pretest patients with a very low PE prevalence (less than 2%) allow- probability. This principle was assessed in 2 recent studies, 15 12 13 ing PE to be ruled out without any testing. However, ap- the YEARS study and PEGeD study. Both studies used 1.0 plied alone or in association with the revised Geneva score, the μg/mL as the D-dimer cutoff value for patients with a low CPP, 28,29 PERC strategy appears to be insufficiently reliable. The and both achieved a very low overall rate of false-negative test- 4PEPS strategy may not have such a limitation. ing. Of note, the PEGeD study was the most recent study and Another means to limit CTPA overuse is to optimize D- has the lowest PE prevalence (7.4%), with 87% of patients hav- 11 13 dimer testing. The ADJUST-PE study prospectively con- ing a low CPP. It should be used with caution in a popula- firmed the safety and utility of an age-adjusted cutoff value tion of patients with a higher PE prevalence. Indeed, recent ex- for patients 50 years or older (Table 1). However, the effect of ternal validation data of the PEGeD and YEARS strategies in 674 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com Patients with pulmonary embolism, % 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research cohorts of European patients suggest a higher failure rate. 4PEPS will be embraced by ED physicians and will lead to a Moreover, since the methods of CPP assessment are different substantial and safe decrease in imaging testing. in the PERC strategy from the other strategies aiming to re- 10-13 duce overtesting, it is difficult to combine them. For ex- Strengths and Limitations ample, to combine the PERC and PEGeD strategies, the phy- Our study has several strengths. We used a bayesian evidence- sician may have to first assess implicit clinical probability based medicine approach to define the prevalence limit in each (gestalt); second, if low, the PERC strategy; and third, if posi- CPP category, based on the predefined safety threshold and on 10,13 34 tive, the revised Wells score. The risk of misuse in clinical the negative likelihood ratio of D-dimer. We followed a well- practice appears to be major and may have an important im- validated method to derive and validate the score and the re- pact on safety. For example, although combining clinical ge- cent recommendations of the International Society of Throm- stalt and the PERC strategy has proven to be safe, the rate of bosis and Hemostasis to assess the safety of the 4PEPS strategy 16,22 failure when combining a low revised Geneva score and a nega- in ruling out PE. The 5 databases of prospective multi- Here lies the tive PERC strategy finding is higher than 5%. center international studies made it possible to define a large main benefit of 4PEPS: a single rule to guide diagnostic strat- derivation cohort, an internal validation cohort, and 2 exter- egy resulting in a substantial reduction in testing, especially nal validation cohorts. The results in terms of calibration and imaging testing. accuracy were very similar to each other, with an AUC around Most of the 4PEPS criteria are included in other rules or 80%. Finally, the safety of the 4PEPS strategy was confirmed scores for CPP assessment. Nevertheless, in our study, some in an external validation cohort with a moderate PE preva- potentially relevant criteria were not statistically associated lence (11.7%) as well as in an external validation cohort with a with a PE diagnosis (pregnancy, history of cancer, chronic re- high PE prevalence (21.5%). This reinforces the generalizabil- spiratory disease, hemoptysis). As the derivation database was ity of our results. large (n = 5588), we do not think that this is caused by a lack Nevertheless, our study has some limitations. The stud- of power. More probably, we suppose that this result reflects ies used to derive and validate 4PEPS were all performed in the fact that physicians suspect PE at a very low threshold in ED settings and so 4PEPS may be not suitable for inpatients. patients with these characteristics. The first stage of the di- Some variables were not systematically collected in these stud- agnostic process is deciding whether to investigate PE or not. ies. They could not be included in our analyses. We also did This is why the PERC strategy needs to be combined with ge- notincludepatientswithmissingvariables.However,thepopu- stalt and why 4PEPS integrates the item PE is the most likely lation for each cohort remains large, and similar results were diagnosis. This criterion is sometimes criticized for a lack of obtained in the sensitivity analyses considering missing 4PEPS objectivity and reproducibility. Nevertheless, it is included in variables as negative. The score comprises 13 criteria that may 9 12 the Wells score and YEARS strategy, is well-known by the be difficult to memorize, reinforcing the usefulness of an ap- ED physicians, and is easier to explain and to use than ge- plication for computer or handheld devices. Additionally, al- stalt. The inclusion of factors decreasing the probability of PE though we used clinical data from several prospective stud- diagnosis as well as factors increasing it allowed us to derive ies, we calculated this new score retrospectively. The 4PEPS a 4-level score that rules out PE when negative. The 4PEPS cali- strategy needs to be formally validated in a prospective imple- bration and accuracy of the 4PEPS appear to be at least simi- mentation study. 8,33 lar to previous CPP scores for PE (Table 4). To facilitate 4PEPS implementation in clinical practice, an internet-application for smartphone and computer has been Conclusions developed (https://peps.shinyapps.io/PEPS/). 4PEPS will be also incorporated in the new version of the decision-support In conclusion, using a bayesian approach, we derived a new software SPEED (Suspected Pulmonary Embolism in 4-level clinical probability score (4PEPS) to help ED physi- Emergency Departments; http://www.thrombus.fr/). We have cians make decisions regarding patients suspected of PE. The previously shown that, compared with posters and pocket accuracy, safety, and efficacy of the 4PEPS strategy were con- cards,suchdecision-supportsystemsavailableonsmartphones firmed in 2 independent external validation cohorts, one with improves diagnostic decision-making and reduces the number a moderate PE prevalence and the other with a high PE preva- of tests to reach a validated diagnostic decision. 4PEPS could lence. For both cohorts, applying 4PEPS resulted in a very low also be integrated in the electronic medical record for rate of diagnostic failure and a substantial reduction in imaging automated calculation. Using such setups, we believe that testing. It should now be tested in a formal outcome study. ARTICLE INFORMATION Author Affiliations: Emergency Department, CHU of Medicine, Indianapolis (Kline); Division of Angers, Institut Mitovasc UMR (CNRS 6015— Angiology and Hemostasis, Department of Internal Accepted for Publication: December 29, 2020. INSERM 1083), UNIV Angers, F-CRIN INNOVTE, Medicine, Faculty of Medicine, Geneva University Published Online: March 3, 2021. Angers, France (Roy, Douillet, Moumneh); Hospital, Geneva, Switzerland (Righini); Ottawa doi:10.1001/jamacardio.2021.0064 Emergency Department, CHU Angers, Angers, Hospital Research Institute, The Ottawa Hospital, Open Access: This is an open access article France (Friou); Emergency Department, Cliniques Division of Hematology, Department of Medicine, distributed under the terms of the CC-BY License. Universitaires Saint Luc, Université Catholique de University of Ottawa, Ottawa, Ontario, Canada ©2021RoyP-Metal. JAMA Cardiology. Louvain, Brussels, Belgium (Germeau); Department (Le Gal); Emergency Department, Cliniques of Emergency Medicine, Indiana University School Universitaires Saint Luc, Université jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 675 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Catholique de Louvain, F-CRIN INNOVTE, Brussels, application. None of the contributors were cohort study. Lancet. 2017;390(10091):289-297. Belgium (Penaloza). compensated for their work. doi:10.1016/S0140-6736(17)30885-1 Author Contributions: Dr Roy had full access to all 13. Kearon C, de Wit K, Parpia S, et al; PEGeD Study REFERENCES of the data in the study and takes responsibility for Investigators. Diagnosis of pulmonary embolism the integrity of the data and the accuracy of the 1. Konstantinides SV, Meyer G, Becattini C, et al; with D-dimer adjusted to clinical probability. N Engl data analysis. ESC Scientific Document Group. 2019 ESC J Med. 2019;381(22):2125-2134. doi:10.1056/ Study concept and design: Roy, Friou, Germeau, guidelines for the diagnosis and management of NEJMoa1909159 Moumneh, Penaloza. acute pulmonary embolism developed in 14. Singh B, Mommer SK, Erwin PJ, Mascarenhas Acquisition, analysis, or interpretation of data:Roy, collaboration with the European Respiratory SS, Parsaik AK. 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N Engl J Med. 1985;313 interpretation of the data; preparation, review, or unnecessary diagnostic testing in emergency (13):793-799. doi:10.1056/NEJM198509263131306 approval of the manuscript; and decision to submit department patients with suspected pulmonary 23. Hosmer DW, Lemeshow S. Applied Logistic the manuscript for publication. embolism. J Thromb Haemost. 2004;2(8):1247-1255. Regression. Wiley; 1989. doi:10.1111/j.1538-7836.2004.00790.x Meeting Presentation: Preliminary results were 24. Harrell FE Jr, Lee KL, Mark DB. Multivariable presented at the ESC Congress 2019; September 3, 11. Righini M, Van Es J, Den Exter PL, et al. prognostic models: issues in developing models, 2019; Paris, France. Age-adjusted D-dimer cutoff levels to rule out evaluating assumptions and adequacy, and pulmonary embolism: the ADJUST-PE study. JAMA. Previous Posting: This manuscript was posted as a measuring and reducing errors. Stat Med. 1996;15 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135 preprint on SSRN. (4):361-387. doi:10.1002/(SICI)1097-0258(19960229) 12. van der Hulle T, Cheung WY, Kooij S, et al; 15:4<361::AID-SIM168>3.0.CO;2-4 Additional Contributions: We are grateful to Céline YEARS study group. Simplified diagnostic Bugli, PhD (Université Catholique de Louvain, 25. Fagan TJ. Letter: nomogram for Bayes theorem. management of suspected pulmonary embolism Brussels, Belgium), for her help in statistical analysis N Engl J Med. 1975;293(5):257. doi:10.1056/ (the YEARS study): a prospective, multicentre, and Jérémie Riou, PhD (CHU Angers, UNIV Angers, NEJM197507312930513 Angers, France), for developing the 4PEPS internet 676 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research 26. DeLong ER, DeLong DM, Clarke-Pearson DL. does not safely exclude pulmonary embolism. pulmonary embolism in the emergency Comparing the areas under two or more correlated J Thromb Haemost. 2011;9(2):300-304. doi:10.1111/ department. Acad Emerg Med. 2014;21(9):949-959. receiver operating characteristic curves: j.1538-7836.2010.04147.x doi:10.1111/acem.12471 a nonparametric approach. Biometrics. 1988;44(3): 30. Kline JA, Hogg MM, Courtney DM, Miller CD, 33. Penaloza A, Verschuren F, Meyer G, et al. 837-845. doi:10.2307/2531595 Jones AE, Smithline HA. D-dimer threshold increase Comparison of the unstructured clinician gestalt, 27. Hutchinson BD, Navin P, Marom EM, Truong with pretest probability unlikely for pulmonary the Wells score, and the revised Geneva score to MT, Bruzzi JF. Overdiagnosis of pulmonary embolism to decrease unnecessary computerized estimate pretest probability for suspected embolism by pulmonary CT angiography. AJRAmJ tomographic pulmonary angiography. J Thromb pulmonary embolism. Ann Emerg Med. 2013;62(2): Roentgenol. 2015;205(2):271-277. doi:10.2214/AJR. Haemost. 2012;10(4):572-581. doi:10.1111/j.1538-7836. 117-124.e2. 14.13938 2012.04647.x 34. Carpenter CR, Raja AS. Arming the bayesian 28. Penaloza A, Verschuren F, Dambrine S, Zech F, 31. Eddy M, Robert-Ebadi H, Richardson L, et al. physician to rule out pulmonary embolism: using Thys F, Roy PM. Performance of the Pulmonary External validation of the YEARS diagnostic evidence-based diagnostics to combat overtesting. Embolism Rule-out Criteria (the PERC rule) algorithm for suspected pulmonary embolism. Acad Emerg Med. 2014;21(9):1036-1038. doi:10. combined with low clinical probability in high J Thromb Haemost. 2020. doi:10.1111/jth.15083 1111/acem.12450 prevalence population. Thromb Res. 2012;129(5): 32. Kline JA, Richardson DM, Than MP, Penaloza A, e189-e193. doi:10.1016/j.thromres.2012.02.016 Roy PM. Systematic review and meta-analysis of 29. Hugli O, Righini M, Le Gal G, et al. The pregnant patients investigated for suspected Pulmonary Embolism Rule-out Criteria (PERC) rule jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 677 Supplemental Online Content Roy P-M, Friou E, Germeau B, et al. Derivation and validation of a 4-level clinical pretest probability score for suspected pulmonary embolism to safely decrease imaging testing. JAMA Cardiol. Published online March 3, 2021. doi:10.1001/jamacardio.2021.0064 eTable. Distribution of 4PEPS among patients and patients with PE in derivation and validation cohorts eFigure. Receiver operating characteristic curves and calibration plots This supplementary material has been provided by the authors to give readers additional information about their work. © 2021 Roy P-M et al. JAMA Cardiology. eTable. Distribution of 4PEPS among patients and patients with PE in derivation and validation cohorts Derivation cohort Internal validation External validation 1 External validation 2 (N=5588) (N=3726) (N=1548) (N=1669) 4PEPS no. with no. with PE no. with no. with No. No. No. No. value PE (%) (%) PE (%) PE (%) 137 2 (1.46) 15 0 (0.00)   3 227 2 (0.88) 34 1 (2.94) 364 5 (1.37) 33 0 (0.00)  2 568 1 (0.18) 104 3 (2.88)  1 660 13 (1.97) 445 9 (2.02) 70 3 (4.29) 209 1 (0.48) 484 18 (3.72) 93 3 (3.23) 0 745 17 (2.28) 265 14 (5.28) 466 18 (3.86) 1 650 26 (4.00) 118 5 (4.24) 215 16 (7.44) 314 18 (5.73) 121 11 (9.09) 2 402 23 (5.72) 136 10 (7.35) 252 26 (10.3) 123 12 (9.76) 3 415 27 (6.51) 128 11 (8.59) 289 26 (9.00) 156 20 (12.8) 4 408 34 (8.33) 103 10 (9.71) 216 27 (12.5) 151 25 (16.6) 5 328 56 (17.1) 116 18 (15.5) 176 39 (22.2) 142 22 (15.5) 6 281 59 (21.0) 65 11 (16.9) 138 37 (26.8) 100 32 (32.0) 7 198 41 (20.8) 73 18 (24.7) 107 38 (35.5) 96 33 (34.4) 8 198 50 (25.3) 45 14 (31.1) 105 46 (43.8) 96 34 (35.4) 9 139 52 (37.4) 56 20 (35.7) 68 27 (39.7) 69 31 (44.9) 10 116 50 (43.1) 45 15 (33.3) 57 29 (50.9) 61 30 (49.2) 11 74 39 (52.7) 30 11 (36.7) 39 21 (53.9) 43 25 (58.1) 12 73 47 (64.4) 20 6 (30.0) 37 25 (67.6) 23 12 (52.2) 13 51 34 (66.7) 8 4 (50.0) 15 10 (66.7) 15 13 (86.7) 14 26 19 (73.1) 7 4 (57.1) 17 11 (64.7) 23 21 (91.3) 15 29 25 (86.2) 10 9 (90.0) © 2021 Roy P-M et al. JAMA Cardiology. eFigure. Receiver operating characteristic curves and calibration plots Receiver operating characteristic curve (Panels 1) and calibration plots (Panels 2) for 4PEPS in the internal validation cohort (Panels A), the first external validation cohort (Panels B) and the second external validation cohort (Panels C). For calibration plots (Panels 2), the grey zone represents the ideal distribution. The distributions of predicted probabilities are shown at the bottom of the graphs. The Hosmer and Lemeshow goodness of fit and Brier score were 0.753 and 0.082, 0.710 and 0.420, and, 0.134 and 0.089, in the internal validation cohort, the first and second external validation cohorts, respectively. © 2021 Roy P-M et al. JAMA Cardiology. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Cardiology American Medical Association

Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing

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Abstract

Research JAMA Cardiology | Original Investigation Derivation and Validation of a 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Pierre-Marie Roy, MD, PhD; Emilie Friou, MD; Boris Germeau, MD; Delphine Douillet, MD; Jeffrey Allen Kline, MD, PhD; Marc Righini, MD, PhD; Grégoire Le Gal, MD, PhD; Thomas Moumneh, MD; Andrea Penaloza, MD, PhD Supplemental content IMPORTANCE In patients with suspected pulmonary embolism (PE), overuse of diagnostic imaging is an important point of concern. OBJECTIVE To derive and validate a 4-level pretest probability rule (4-Level Pulmonary Embolism Clinical Probability Score [4PEPS]) that makes it possible to rule out PE solely on clinical criteria and optimized D-dimer measurement to safely decrease imaging testing for suspected PE. DESIGN, SETTING, AND PARTICIPANTS This study included consecutive outpatients suspected of having PE from US and European emergency departments. Individual data from 3 merged management studies (n = 11 114; overall prevalence of PE, 11%) were used for the derivation cohort and internal validation cohort. The external validation cohorts were taken from 2 independent studies, the first with a high PE prevalence (n = 1548; prevalence, 21.5%) and the second with a moderate PE prevalence (n = 1669; prevalence, 11.7%). A prior definition of pretest probability target values to achieve a posttest probability less than 2% was used on the basis of the negative likelihood ratios of D-dimer. Data were collected from January 2003 to April 2016, and data were analyzed from June 2018 to August 2019. MAIN OUTCOMES AND MEASURES The rate of PE diagnosed during the initial workup or during follow-up and the rate of imaging testing. RESULTS Of the 5588 patients in the derivation cohort, 3441 (61.8%) were female, and the mean (SD) age was 52 (18.5) years. The 4PEPS comprises 13 clinical variables scored from −2 to 5. It results in the following strategy: (1) very low probability of PE if 4PEPS is less than 0: PE ruled out without testing; (2) low probability of PE if 4PEPS is 0 to 5: PE ruled out if D-dimer level is less than 1.0 μg/mL; (3) moderate probability of PE if 4PEPS is 6 to 12: PE ruled out if D-dimer level is less than the age-adjusted cutoff value; (4) high probability of PE if 4PEPS is greater than 12: PE ruled out by imaging without preceding D-dimer test. In the first and the second external validation cohorts, the area under the receiver operator characteristic curves were 0.79 (95% CI, 0.76 to 0.82) and 0.78 (95% CI, 0.74 to 0.81), respectively. The false-negative testing rates if the 4PEPS strategy had been applied were 0.71% (95% CI, 0.37 to 1.23) and 0.89% (95% CI, 0.53 to 1.49), respectively. The absolute reductions in imaging testing were −22% (95% CI, −26 to −19) and −19% (95% CI, −22 to −16) in the first and second external validation cohorts, respectively. The 4PEPS strategy compared favorably with all recent strategies in terms of imaging testing. CONCLUSIONS AND RELEVANCE The 4PEPS strategy may lead to a substantial and safe reduction in imaging testing for patients with suspected PE. It should now be tested in a formal outcome study. Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Pierre-Marie Roy, MD, PhD, Emergency Department, CHU Angers, Institut Mitovasc UMR (CNRS 6015—INSERM 1083), UNIV Angers, F-CRIN INNOVTE, 4 Rue Larrey, 49933 JAMA Cardiol. 2021;6(6):669-677. doi:10.1001/jamacardio.2021.0064 Angers, France (pmroy@ Published online March 3, 2021. chu-angers.fr). (Reprinted) 669 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing espite the significant progress of the last decades, di- agnosing pulmonary embolism (PE) remains a clini- Key Points D cal challenge. The standard diagnostic strategy, based Question Can a pretest probability score make it possible to rule on clinical probability assessment, D-dimer testing, and com- out pulmonary embolism solely on clinical criteria and optimized puted tomography pulmonary angiography (CTPA), is proven D-dimer measurement to safely decrease imaging testing? to have a very low rate of diagnostic failure. However, there Findings In this study, the 4-Level Pulmonary Embolism Clinical 2,3 has been a large increase in CTPA for suspected PE. The ex- Probability Score (4PEPS) was derived and validated using act reasons are likely multifactorial. The signs and symptoms databases from 3 merged management studies. The safety and the of PE are very common and unspecific. As such, clinicians fear efficacy of the 4PEPS strategy was confirmed in 2 external they might be missing a life-threatening condition and are validation cohorts (false-negative rates: 0.71% and 0.89%; absolute reductions in imaging testing: −19% and −22%, prone to initiate a diagnostic process. Due to the lack of speci- respectively). ficity of D-dimer testing, a large proportion of patients have a false-positive result and require imaging to rule out PE. Fi- Meaning The 4PEPS strategy may lead to a substantial and safe nally, CTPA is readily available, fast, minimally invasive, and reduction in imaging testing for patients with suspected pulmonary embolism. more sensitive than ventilation/perfusion (V/Q) scans. A slight increase in PE diagnosis has been observed as a result but with no clear benefits in terms of outcome, especially PE-related established using the results of the YEARS study and the Age- 4,5 mortality. One explanation is that because more CTPAs are Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Em- being performed, there is a greater risk of false-positive re- bolism (ADJUST-PE) study. They were found to be 0.08 and sults or non–clinically relevant diagnoses. Moreover, CTPA ex- 0.01, respectively. Accordingly, to achieve a posttest probabil- poses patients to risks of allergies, kidney failure, and cumu- ity less than 2%, the upper limit of PE prevalence was set at 6,7 lative radiation-induced cancer. Several strategies have 20% for low CPP and at 65% for moderate CPP. The present therefore been proposed to reduce PE overtesting and over- study was a retrospective analysis of data prospectively col- 4,8-14 diagnosis(Table 1). Thesehaveprovedsatisfactoryinterms lected in 5 studies that were all approved by an ethical com- of safety and efficacy, but they are based on different meth- mittee and performed with the informed consent of the par- ods of assessing clinical pretest probability (CPP; eg, Wells or ticipating patients. According to the current European revised Geneva scores for PE, Pulmonary Embolism Rule- legislation, an approval of an ethical committee was not re- 10 12 out Criteria [PERC] strategy, or YEARS strategy ), thus mak- quired for the present study. ing it difficult to combine them and increasing the risk of mis- use in clinical practice. Source of Data Our primary aim was to develop and validate a pretest For the derivation and internal validation, we merged 3 pro- probability score to safely reduce imaging testing by integrat- spectively collected databases from patients with suspected ing all the previously proposed strategies: the 4-Level Pulmo- PE (n = 11 114). The first study was performed in 117 emer- nary Embolism Clinical Probability Score (4PEPS). Our sec- gency departments (EDs) in France and Belgium (n = 1529; en- ondary goal was to retrospectively assess the safety of a rolled in 2003) ; the second study was performed in 20 French diagnostic strategy based on this new score and its efficacy in EDs (n = 1645; enrolled in 2005 to 2006) ; and the third study reducing imaging testing. was performed in 12 EDs in the US (n = 7940; enrolled in 2003 to 2006). Each database was randomly split into 2 groups, including 60% for the derivation cohort and 40% for the in- ternal validation cohort. Methods Two other databases were used for external validation. The Study Design first study was performed in 6 EDs in France, Belgium, and Four levels of CPP for 4PEPS were defined a priori: Switzerland (n = 1819; enrolled in 2005 to 2006) and the sec- • Very low CPP, allowing exclusion of PE on clinical criteria only. ond in 12 EDs in France and Belgium (n = 1757; enrolled in 2015 • Low CPP, allowing exclusion of PE with a high-sensitivity to 2016). D-dimer level less than 1.0 μg/mL (to convert to nanomoles per liter, multiply by 5.476). Outcome • Moderate CPP, allowing exclusion of PE with a D-dimer level The outcome was a PE diagnosed on CTPA or high- less than 0.5 μg/mL or less than the age-adjusted cutoff value probability V/Q scan during the initial diagnostic workup or a (calculated as age × 0.01 μg/mL for patients older than venous thromboembolism (VTE) occurring during follow-up 50 years). (3 months for the 4 European studies and 45 days for the US • High CPP, not allowing a safe exclusion of PE with D-dimer study) in a patient in whom PE was initially ruled out. In all testing and requiring imaging testing (CTPA or V/Q scan). studies, the following were considered as VTE: symptomatic To derive the score, we predefined the upper limit for PE PE objectively confirmed with CTPA or high-probability V/Q prevalence in each CPP category using the bayesian approach scan and/or deep vein thrombosis on compression ultraso- 13,15,16 and considered 2% as the safety threshold for PE. The nography and/or sudden unexpected death potentially negative likelihood ratios of a D-dimer test using 1.0 μg/mL as related to PE according to an independent adjudication the cutoff value and using an age-adjusted cutoff value were committee. 670 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research Table 1. Diagnostic Strategy Aiming to Reduce Imaging Testing PE strategy No diagnostic test required D-dimer test required D-dimer cutoff value CTPA or V/Q scan required Standard NA Nonhigh CPP with RG score (0-10), <0.5 μg/mL High CPP or positive D-dimer a,b Wells score (0-4), or gestalt test result PERC strategy Low CPP with gestalt and Low CPP and positive PERC score (>0) <0.5 μg/mL High CPP or positive D-dimer negative PERC score (0) or intermediate CPP with gestalt test result a d ADJUST-PE NA Nonhigh CPP with RG score (0-10) Age adjusted High CPP or positive D-dimer d a strategy or Wells score (0-4) test result e e YEARS strategy NA YEARS score negative (0) <1.0 μg/mL Positive D-dimer test result YEARS score positive (>0) <0.5 μg/mL f b PEGeD strategy NA Low CPP with Wells score (0-4) <1.0 μg/mL High CPP or positive D-dimer test result Moderate CPP with Wells score (4.5-6) <0.5 μg/mL 4PEPS Very low CPP with 4PEPS (<0) Low CPP with 4PEPS (0-5) <1.0 μg/mL High CPP with 4PEPS (>12) or positive D-dimer test result Moderate CPP 4PEPS (6-12) Age adjusted Abbreviations: 4PEPS, 4-Level Pulmonary Embolism Clinical Probability Score; beats per minute (+1.5), clinical signs of deep venous thrombosis (+3), PE is the ADJUST-PE, Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary most likely diagnosis (+3). Embolism; CPP, clinical pretest probability; CTPA, computed tomography PERC strategy: age of 50 years or older (+1), heart rate of 100 beats per minute pulmonary angiography; PE, pulmonary embolism; PEGeD, Pulmonary or greater (+1), room air pulse oximetry less than 95% (+1), unilateral leg Embolism Graduated d-Dimer; PERC, Pulmonary Embolism Rule-out Criteria; edema (+1), hemoptysis (+1), recent surgery or trauma in the past 4 weeks RG, revised Geneva; V/Q, ventilation/perfusion. 10 (+1). SI conversion factor: To convert D-dimer to nanomoles per liter, multiply d ADJUST-PE strategy study: age-adjusted D-dimer cutoff value less than 0.5 by 5.476. μg/mL for patients younger than 50 years and calculated as age × 0.01 μg/mL a 11 RG score: age of 65 years or older (+1), previous deep venous thrombosis or PE for patients 50 years or older. (+3), surgery or lower limb fracture in the past month (+2), active cancer (+2), e YEARS strategy: 3-factor clinical rule derived from revised Wells score for PE, unilateral lower limb pain (+3), hemoptysis (+2), heart rate of 75 to 94 beats including clinical signs of deep vein thrombosis (+1), hemoptysis (+1), and PE is per minute (+3) or 95 beats per minute or greater (+5), pain on lower limb 12 the most likely diagnosis (+1). deep venous palpation and unilateral edema (+4). f 13 PEGeD strategy: strategy using the 3-level revised Wells score for PE. Wells score (revised Wells score for PE): active cancer (+1), surgery or Age-adjusted cutoff value less than 0.5 μg/mL for patients younger than 50 bedridden for 3 or more days during the past 4 weeks (+1.5), previous deep years and calculated as age × 0.01 μg/mL for patients 50 years or older. venous thrombosis or PE (+1.5), hemoptysis (+1), heart rate greater than 100 We performed a stepwise backward analysis including 1 4PEPS Derivation 23,24 We evaluated all of the clinical variables known to be poten- variable for every 10 VTE events. We then removed the tially associated with PE and available in the database. As pa- nonsignificant variables, considering a 2-tailed P value less tients were suspected of PE because of dyspnea or chest pain, than .05 as significant. Only significant variables were left in these variables were not included. However, we took the vari- the final score. We assigned points for the score according to able of dyspnea and chest pain into account when both were the regression coefficients. Finally, we chose the cutoff val- present in a given patient. Variables with more than 2% of miss- ues to achieve the predefined levels of PE prevalence in ing data were excluded, except those included in other pre- each CPP category. 10 8 diction rules (PERC strategy, revised Geneva score, and Wells score ). Namely, the following variables were excluded: his- 4PEPS Validation tory of hypertension, diabetes, dyslipidemia, coronary dis- The accuracy of the score was assessed by calculating the re- ease, long travel, chronic kidney failure, smoking, family his- ceiver operating characteristic curve and analyzing the area un- tory of VTE, body weight, respiratory rate, and antiplatelet der the receiver operating characteristic curve (AUC). The AUC treatment. We categorized the continuous variables accord- confidence interval was computed with the DeLong-DeLong ing to the cutoff values previously chosen in other scoring sys- method. Calibration was assessed with the Hosmer- tems and according to their clinical relevance. There were 4 Lemeshow goodness-of-fit statistic. A Brier score was also categories for age (younger than 50 years, aged 50 to 64 years, reported, summarizing the magnitude of error in the probabil- aged 65 to 80 years, and older than 80 years), 3 categories for ity forecasts as between 0.0 and 1.0, where a perfectly cali- heart rate (less than 80 beats per minute, 80 to 100 beats per brated model would score 0.0. minute, and more than 100 beats per minute) and tempera- ture (less than 38 °C, 38 to 39 °C, and greater than 39 °C), and 4PEPS Strategy Safety and Efficacy Assessment 2 categories for systolic blood pressure (less than 90 mm Hg The safety of the 4PEPS strategy was retrospectively as- and 90 mm Hg or greater) and pulse oximetry (Spo ; less than sessed using the false-negative rate if the strategy had been 95% and 95% or greater). applied in the 2 external validation cohorts. This is the rate of To select the predictor variables associated with PE, we PE diagnoses during the initial diagnostic process or VTEs 2 22 performed a univariate analysis by using the χ test. All found during the 3-month follow-up among patients with a variables with a 2-tailed P value less than .20 as well as the very low CPP, a low CPP and D-dimer level less than 1.0 μg/ nonsignificant variables included in other prediction rules mL, a moderate CPP and D-dimer level less than the age- were included in a multivariate logistic regression model. adjusted cutoff value, or a negative CTPA or V/Q scan. jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 671 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Table 2. Baseline Characteristics of the Patients in the Different Cohorts Cohort, No. (%) External validation Internal Moderate Derivation validation High prevalence prevalence Characteristic (n = 5588) (n = 3726) (n = 1548) (n = 1669) Demographic characteristics Age, mean (SD), y 52 (18.5) 52 (18.5) 59 (18.7) 53 (19.8) Male 2147 (38.4) 1461 (39.2) 706 (45.6) 699 (41.9) Treatment and medical history Hormonal estrogenic treatment 417 (7.5) 272 (7.3) 132 (8.5) 189 (11.3) History of VTE 705 (12.6) 486 (13.0) 266 (17.2) 199 (11.9) Current malignancy 688 (12.3) 403 (10.8) 114 (7.4) 133 (8.0) Chronic respiratory disease 1121 (20.1) 724 (19.4) 193 (12.5) 139 (8.3) Chronic heart failure 532 (9.5) 330 (8.9) 82 (5.3) 94 (5.6) Immobility within 4 wk 819 (14.7) 523 (14.0) 225 (14.6) 200 (12.0) Pregnancy 83 (1.5) 61 (1.6) 0 15 (0.9) Postpartum within 4 wk 84 (1.5) 48 (1.3) 12 (0.8) 9 (0.5) Symptoms Chest pain 3572 (63.9) 2363 (63.4) 1070 (69.1) 1103 (66.1) Dyspnea 3809 (68.2) 2545 (68.3) 1108 (71.6) 927 (55.5) Abbreviations: DVT, deep vein thrombosis; PE, pulmonary Chest pain and dyspnea 2323 (41.6) 1570 (42.1) 704 (45.5) 479 (28.7) embolism; VTE, venous Syncope 496 (8.9) 328 (8.8) 321 (20.7) 315 (18.9) thromboembolism. Clinically suspected DVT 620 (11.1) 403 (10.8) 270 (17.4) 242 (14.5) Cancer or treatment for cancer within 1 year. Hemoptysis 187 (3.4) 123 (3.3) 71 (4.6) 47 (2.8) Surgery, lower limb plaster cast, or Signs, mean (SD) bedridden more than 3 days for Heart rate, beats per minute 92 (21.3) 92 (20.8) 8.7 (19.8) 87 (19.5) acute medical condition within the last 4 weeks. Systolic blood pressure, mm Hg 133 (24.6) 133 (24.9) 139 (22.4) 136 (21.2) Unilateral lower limb spontaneous Room air pulse oximetry, % 96 (4.7) 96 (4.4) 95 (5.0) 96 (3.7) pain, pain on deep vein palpation, or Temperature, °C 36.8 (0.7) 36.8 (0.7) 37.1 (1.3) 36.8 (0.7) swelling. PE is the most likely diagnosis 1169 (20.9) 774 (20.7) 718 (46.4) 348 (20.9) PE diagnosed during the initial diagnostic workup or symptomatic Final PE prevalence 615 (11.0) 432 (11.6) 332 (21.5) 196 (11.7) VTE occurred during the follow-up. We defined the safety threshold of the 4PEPS strategy as ables of 4PEPS as negative, ie, resulting in the lowest score and a function of PE prevalence applying the recommendations of so representing the highest risk of a false-negative finding using the International Society of Thrombosis and Hemostasis the 4PEPS strategy. (1.82 + [0.00528 × prevalence]). The respective PE preva- lences in the first and second external validation cohorts were Statistical Analysis 21.4% and 11.7%, respectively. Thus, the acceptable upper lim- We calculated the 95% CIs by using the Mid-P exact value per- itsofthe95%CIoffalse-negativerateswerepredefinedat1.93% formed using OpenEpi version 2, an open-source calculator. and 1.88%, respectively. All other statistical analyses were performed using SPSS ver- Finally, the efficacy of the 4PEPS strategy was assessed by sion 25.0 (SPSS Inc). the rate of D-dimer and imaging testing, mainly CTPA, that could have been avoided if the 4PEPS strategy had been ap- plied compared with the standard strategy, the PERC strategy, Results 11 12 the ADJUST-PE strategy, the YEARS strategy, and the Pul- monary Embolism Graduated D-Dimer (PEGeD) strategy After exclusion of patients with missing data, 5588 patients (Table 1). were included in the derivation cohort (PE prevalence, 11.0%), 3726 in the internal validation cohort (PE prevalence, 11.7%), 1548 in the first external validation cohort (PE prevalence, 21.5), Missing Data Analyses were performed including all analyzable patients. Pa- and 1669 in the second external validation cohort (PE preva- tients with missing data were excluded and no imputation was lence, 11.7%). Of the 5588 patients in the derivation cohort, 3441 performed. However, a sensitivity analysis was carried out for (61.8%) were female, and the mean (SD) age was 52 (18.5) years. the 2 external validation cohorts considering the missing vari- In the 3 validation cohorts, 2265 of 3726 (60.7%), 842 of 1548 672 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research (54.4%), and 970 of 1669 (58.1%) were female, and the mean Table 3. 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) (SD) age was 52 (18.5), 59 (18.7), and 53 (19.8) years, respec- Regression tively. Characteristics of the study samples are presented in Variable coefficient Points Table 2. Age, y <50 −0.993 −2 4PEPS Derivation 50-64 −0.656 −1 A univariate analysis found a statistical association with PE di- Chronic respiratory disease −0.570 −1 agnosis for 21 variables. All of these were included in the mul- Heart rate <80 beats per minute −0.406 −1 tivariate regression. In addition, we included the variable of Chest pain and acute dyspnea 0.297 1 estrogenic treatment since this criterion is present in the PERC Male 0.472 2 strategy. In the multivariate model, age of 65 to 80 years or Hormonal estrogenic treatment 0.608 2 older than 80 years, pulse rate of 80 to 100 beats per minute, Personal history of VTE 0.711 2 systolic arterial pressure, hemoptysis, cancer, chronic car- Syncope 0.504 2 diac failure, and pregnancy or post partum were not indepen- Immobility within the last 4 wk 0.509 2 dently associated with PE. The remaining 13 variables were in- Pulse oxygen saturation <95% 0.832 3 cluded in the final model, and we assigned points for each of Calf pain and/or unilateral lower limb edema 1.009 3 them according to their regression coefficient. Table 3 repre- PE is the most likely diagnosis 1.860 5 sents the final model (4PEPS). Clinical probability, total The PE prevalence by 4PEPS and the distribution of 4PEPS Very low CPP (<2%): PE can be ruled out <0 in the derivation cohort are presented in the Figure and the eTable in the Supplement. According to the predefined cutoff Low CPP (2%-20%): PE can be ruled 0-5 out if D-dimer level <1.0 μg/mL values, a 4PEPS less than 0 corresponds to a very low CPP (less Moderate CPP (20%-65%): PE can be 6-12 than 2%), a 4PEPS of 0 to 5 corresponds to a low CPP (less than ruled out if D-dimer level <0.5 μg/mL or <(age × 0.01) μg/mL 20%), a 4PEPS of 6 to 12 corresponds to a moderate CPP (less High CPP (>65%): PE cannot be ruled out ≥13 than 65%), and a 4PEPS greater than 12 corresponds to a high without imaging testing CPP (65% or greater) (Table 3). PE prevalence in the very low Abbreviations: CPP, clinical pretest probability; PE, pulmonary embolism; VTE, category was 1.1% (95% CI, 0.6-1.6); low category, 6.2% (95% venous thromboembolism. CI, 5.3-7.1); intermediate category, 31.3% (95% CI, 28.6-34.1); SI conversion factor: To convert D-dimer to nanomoles per liter, multiply by and high category, 73.6% (95% CI, 65.2-82.0). 5.476. Surgery, lower limb plaster cast, or bedridden more than 3 days for acute medical condition within the last 4 weeks. 4PEPS Validation For the 3 validation cohorts, the PE prevalence by 4PEPS and the distribution of the 4PEPS are presented in the Figure and Compared with the standard strategy (CPP assessed using the eTable in the Supplement. In the internal validation co- the revised Geneva score, D-dimer measurement with 0.5 hort, the AUC was 0.83 (95% CI, 0.81-0.85). In the first and sec- μg/mL as the cutoff value), applying 4PEPS would have de- ond external validation cohort, the AUCs were 0.79 (95% CI, creased the CTPA rate (external validation cohort 1: 46% vs 0.76-0.82) and 0.78 (95% CI, 0.74-0.81), respectively. The AUCs 68%; difference, −22%; 95% CI, −26 to −19; external valida- and the degree of concordance between the observed and tion cohort 2: 32% vs 51%; difference, −19%; 95% CI, −22 to −16). 10-13 predicted prevalence are presented in the eFigure in the Table 4 compares the different strategies proposed to re- Supplement. duce diagnostic testing. 4PEPS Strategy Validation When the 4PEPS strategy was retrospectively applied in the Discussion first and second external validation cohorts, the false- negative rates were 11 of 1548 (0.71%; 95% CI, 0.37-1.23) and Using 5 multicenter cohorts regrouping more than 12 000 pa- 14 of 1570 (0.89%; 95% CI, 0.53-1.49), respectively. No fatal PE tients suspected of PE, we were able to derive and validate a or high-risk hemodynamically unstable PE were observed, and new clinical probability score to help physicians diagnose PE 3 of 11 false-negative VTEs in the high-prevalence cohort and and safely decrease diagnostic imaging. Applying the 4PEPS 3 of 14 false-negative VTEs in the moderate-prevalence co- diagnostic strategy retrospectively to 2 external validation co- hort were subsegmental PE. The upper limit of the 95% CI of horts, the rate of false-negative tests was below 1%, and the the false-negative rate was less than the predefined cutoff value 4PEPS strategy performed better than all previously pro- to consider the 4PEPS strategy as safe in the first (1.93%) and posed strategies in terms of reducing imaging testing. second (1.88%) external validation cohorts. Similar results were Overuse of CTPA for suspected PE is an important concern. observed in the sensitivity analyses considering missing vari- There is increasing evidence that CTPA is frequently used in- ables of 4PEPS as negative (high-prevalence cohort: 11 of 1687; appropriately in patients for whom the benefits (probability false-negative rate, 0.65%; 95% CI, 0.34-1.13; moderate- of PE diagnosis and avoiding a PE complication) are out- prevalence cohort: 14 of 1655; false-negative rate, 0.85%; 95% weighed by the risks (probability of a false-positive result, com- CI, 0.50-1.61). plication of anticoagulation, short-term or long-term adverse jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 673 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Figure. Pulmonary Embolism Prevalence by 4-Level Pulmonary Embolism Clinical Probability Score (4PEPS) in the Derivation and Validation Cohorts Derivation cohort Internal validation cohort External validation cohort 1 External validation cohort 2 ≤–3 –2 –1 0 123456789 10 11 12 13 14 ≥15 4-Level Pulmonary Embolism Clinical Probability Score Table 4. Diagnostic Tests and False-Negative Testing According to the Strategy Retrospectively Applied External validation cohort, No. (%) High prevalence (n = 1546) Moderate prevalence (n = 1555) Strategy D-dimer test CTPA or V/Q scan False-negatives D-dimer test CTPA or V/Q scan False-negatives Standard 1474 (95.3) 1058 (68.4) 4 (0.2) 1517 (97.6) 795 (51.1) 0 PERC strategy 1188 (76.7) 981 (63.4) 16 (1.0) 1143 (73.5) 758 (48.7) 4 (0.3) ADJUST-PE strategy 1474 (95.3) 890 (57.6) 5 (0.3) 1517 (97.6) 714 (45.9) 0 YEARS strategy 1546 (100) 885 (58.2) 11 (0.7) 1555 (100) 582 (37.4) 9 (0.6) PEGeD strategy 1429 (92.4) 817 (52.9) 12 (0.8) 1485 (95.5) 553 (35.6) 11 (0.7) 4PEPS 1341 (86.7) 713 (46.1) 11 (0.7) 1198 (77.0) 499 (32.1) 14 (0.9) Abbreviations: 4PEPS, 4-Level Pulmonary Embolism Clinical Probability Score; Pulmonary Embolism Graduated d-Dimer; PERC, Pulmonary Embolism Rule-out ADJUST-PE, Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Criteria; V/Q, ventilation/perfusion. Embolism; CTPA, computed tomography pulmonary angiography; PEGeD, 2,3,27 effect of CTPA). The first strategy developed to deal with the ADJUST-PE strategy on imaging testing rates remains lim- 10,15 overtesting was the PERC strategy. This can be used for pa- ited (−10.8% or −5.2% in our high-prevalence and moderate- tients for whom the clinician has already established alow clini- prevalence external validation cohorts, respectively), particu- cal probability of PE based on an implicit gestalt impression. larly in young patients. A further proposal, based on the Bayes A negative PERC strategy finding defines a subgroup of these theorem, is to adjust the D-dimer cutoff value to the pretest patients with a very low PE prevalence (less than 2%) allow- probability. This principle was assessed in 2 recent studies, 15 12 13 ing PE to be ruled out without any testing. However, ap- the YEARS study and PEGeD study. Both studies used 1.0 plied alone or in association with the revised Geneva score, the μg/mL as the D-dimer cutoff value for patients with a low CPP, 28,29 PERC strategy appears to be insufficiently reliable. The and both achieved a very low overall rate of false-negative test- 4PEPS strategy may not have such a limitation. ing. Of note, the PEGeD study was the most recent study and Another means to limit CTPA overuse is to optimize D- has the lowest PE prevalence (7.4%), with 87% of patients hav- 11 13 dimer testing. The ADJUST-PE study prospectively con- ing a low CPP. It should be used with caution in a popula- firmed the safety and utility of an age-adjusted cutoff value tion of patients with a higher PE prevalence. Indeed, recent ex- for patients 50 years or older (Table 1). However, the effect of ternal validation data of the PEGeD and YEARS strategies in 674 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com Patients with pulmonary embolism, % 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research cohorts of European patients suggest a higher failure rate. 4PEPS will be embraced by ED physicians and will lead to a Moreover, since the methods of CPP assessment are different substantial and safe decrease in imaging testing. in the PERC strategy from the other strategies aiming to re- 10-13 duce overtesting, it is difficult to combine them. For ex- Strengths and Limitations ample, to combine the PERC and PEGeD strategies, the phy- Our study has several strengths. We used a bayesian evidence- sician may have to first assess implicit clinical probability based medicine approach to define the prevalence limit in each (gestalt); second, if low, the PERC strategy; and third, if posi- CPP category, based on the predefined safety threshold and on 10,13 34 tive, the revised Wells score. The risk of misuse in clinical the negative likelihood ratio of D-dimer. We followed a well- practice appears to be major and may have an important im- validated method to derive and validate the score and the re- pact on safety. For example, although combining clinical ge- cent recommendations of the International Society of Throm- stalt and the PERC strategy has proven to be safe, the rate of bosis and Hemostasis to assess the safety of the 4PEPS strategy 16,22 failure when combining a low revised Geneva score and a nega- in ruling out PE. The 5 databases of prospective multi- Here lies the tive PERC strategy finding is higher than 5%. center international studies made it possible to define a large main benefit of 4PEPS: a single rule to guide diagnostic strat- derivation cohort, an internal validation cohort, and 2 exter- egy resulting in a substantial reduction in testing, especially nal validation cohorts. The results in terms of calibration and imaging testing. accuracy were very similar to each other, with an AUC around Most of the 4PEPS criteria are included in other rules or 80%. Finally, the safety of the 4PEPS strategy was confirmed scores for CPP assessment. Nevertheless, in our study, some in an external validation cohort with a moderate PE preva- potentially relevant criteria were not statistically associated lence (11.7%) as well as in an external validation cohort with a with a PE diagnosis (pregnancy, history of cancer, chronic re- high PE prevalence (21.5%). This reinforces the generalizabil- spiratory disease, hemoptysis). As the derivation database was ity of our results. large (n = 5588), we do not think that this is caused by a lack Nevertheless, our study has some limitations. The stud- of power. More probably, we suppose that this result reflects ies used to derive and validate 4PEPS were all performed in the fact that physicians suspect PE at a very low threshold in ED settings and so 4PEPS may be not suitable for inpatients. patients with these characteristics. The first stage of the di- Some variables were not systematically collected in these stud- agnostic process is deciding whether to investigate PE or not. ies. They could not be included in our analyses. We also did This is why the PERC strategy needs to be combined with ge- notincludepatientswithmissingvariables.However,thepopu- stalt and why 4PEPS integrates the item PE is the most likely lation for each cohort remains large, and similar results were diagnosis. This criterion is sometimes criticized for a lack of obtained in the sensitivity analyses considering missing 4PEPS objectivity and reproducibility. Nevertheless, it is included in variables as negative. The score comprises 13 criteria that may 9 12 the Wells score and YEARS strategy, is well-known by the be difficult to memorize, reinforcing the usefulness of an ap- ED physicians, and is easier to explain and to use than ge- plication for computer or handheld devices. Additionally, al- stalt. The inclusion of factors decreasing the probability of PE though we used clinical data from several prospective stud- diagnosis as well as factors increasing it allowed us to derive ies, we calculated this new score retrospectively. The 4PEPS a 4-level score that rules out PE when negative. The 4PEPS cali- strategy needs to be formally validated in a prospective imple- bration and accuracy of the 4PEPS appear to be at least simi- mentation study. 8,33 lar to previous CPP scores for PE (Table 4). To facilitate 4PEPS implementation in clinical practice, an internet-application for smartphone and computer has been Conclusions developed (https://peps.shinyapps.io/PEPS/). 4PEPS will be also incorporated in the new version of the decision-support In conclusion, using a bayesian approach, we derived a new software SPEED (Suspected Pulmonary Embolism in 4-level clinical probability score (4PEPS) to help ED physi- Emergency Departments; http://www.thrombus.fr/). We have cians make decisions regarding patients suspected of PE. The previously shown that, compared with posters and pocket accuracy, safety, and efficacy of the 4PEPS strategy were con- cards,suchdecision-supportsystemsavailableonsmartphones firmed in 2 independent external validation cohorts, one with improves diagnostic decision-making and reduces the number a moderate PE prevalence and the other with a high PE preva- of tests to reach a validated diagnostic decision. 4PEPS could lence. For both cohorts, applying 4PEPS resulted in a very low also be integrated in the electronic medical record for rate of diagnostic failure and a substantial reduction in imaging automated calculation. Using such setups, we believe that testing. It should now be tested in a formal outcome study. ARTICLE INFORMATION Author Affiliations: Emergency Department, CHU of Medicine, Indianapolis (Kline); Division of Angers, Institut Mitovasc UMR (CNRS 6015— Angiology and Hemostasis, Department of Internal Accepted for Publication: December 29, 2020. INSERM 1083), UNIV Angers, F-CRIN INNOVTE, Medicine, Faculty of Medicine, Geneva University Published Online: March 3, 2021. Angers, France (Roy, Douillet, Moumneh); Hospital, Geneva, Switzerland (Righini); Ottawa doi:10.1001/jamacardio.2021.0064 Emergency Department, CHU Angers, Angers, Hospital Research Institute, The Ottawa Hospital, Open Access: This is an open access article France (Friou); Emergency Department, Cliniques Division of Hematology, Department of Medicine, distributed under the terms of the CC-BY License. Universitaires Saint Luc, Université Catholique de University of Ottawa, Ottawa, Ontario, Canada ©2021RoyP-Metal. JAMA Cardiology. Louvain, Brussels, Belgium (Germeau); Department (Le Gal); Emergency Department, Cliniques of Emergency Medicine, Indiana University School Universitaires Saint Luc, Université jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 675 Research Original Investigation 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Catholique de Louvain, F-CRIN INNOVTE, Brussels, application. None of the contributors were cohort study. Lancet. 2017;390(10091):289-297. Belgium (Penaloza). compensated for their work. doi:10.1016/S0140-6736(17)30885-1 Author Contributions: Dr Roy had full access to all 13. Kearon C, de Wit K, Parpia S, et al; PEGeD Study REFERENCES of the data in the study and takes responsibility for Investigators. Diagnosis of pulmonary embolism the integrity of the data and the accuracy of the 1. Konstantinides SV, Meyer G, Becattini C, et al; with D-dimer adjusted to clinical probability. N Engl data analysis. ESC Scientific Document Group. 2019 ESC J Med. 2019;381(22):2125-2134. doi:10.1056/ Study concept and design: Roy, Friou, Germeau, guidelines for the diagnosis and management of NEJMoa1909159 Moumneh, Penaloza. acute pulmonary embolism developed in 14. Singh B, Mommer SK, Erwin PJ, Mascarenhas Acquisition, analysis, or interpretation of data:Roy, collaboration with the European Respiratory SS, Parsaik AK. 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Dr Le Gal has (9):831-837. doi:10.1001/archinternmed.2011.178 (3):157-164. doi:10.7326/0003-4819-144-3- received grants from the French Health Ministry, 200602070-00003 6. Mitchell AM, Jones AE, Tumlin JA, Kline JA. Portola Pharmaceuticals, Boehringer Ingelheim, Prospective study of the incidence of 18. Roy PM, Durieux P, Gillaizeau F, et al. Pfizer, Bristol Myers Squibb, LEO Pharma, Daiichi contrast-induced nephropathy among patients A computerized handheld decision-support system Sankyo, and Bayer as well as personal fees from evaluated for pulmonary embolism by to improve pulmonary embolism diagnosis: Bayer, Pfizer, LEO Pharma, Sanofi, and bioMérieux. contrast-enhanced computed tomography. Acad a randomized trial. 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N Engl J Med. 1985;313 interpretation of the data; preparation, review, or unnecessary diagnostic testing in emergency (13):793-799. doi:10.1056/NEJM198509263131306 approval of the manuscript; and decision to submit department patients with suspected pulmonary 23. Hosmer DW, Lemeshow S. Applied Logistic the manuscript for publication. embolism. J Thromb Haemost. 2004;2(8):1247-1255. Regression. Wiley; 1989. doi:10.1111/j.1538-7836.2004.00790.x Meeting Presentation: Preliminary results were 24. Harrell FE Jr, Lee KL, Mark DB. Multivariable presented at the ESC Congress 2019; September 3, 11. Righini M, Van Es J, Den Exter PL, et al. prognostic models: issues in developing models, 2019; Paris, France. Age-adjusted D-dimer cutoff levels to rule out evaluating assumptions and adequacy, and pulmonary embolism: the ADJUST-PE study. JAMA. Previous Posting: This manuscript was posted as a measuring and reducing errors. Stat Med. 1996;15 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135 preprint on SSRN. (4):361-387. doi:10.1002/(SICI)1097-0258(19960229) 12. van der Hulle T, Cheung WY, Kooij S, et al; 15:4<361::AID-SIM168>3.0.CO;2-4 Additional Contributions: We are grateful to Céline YEARS study group. Simplified diagnostic Bugli, PhD (Université Catholique de Louvain, 25. Fagan TJ. Letter: nomogram for Bayes theorem. management of suspected pulmonary embolism Brussels, Belgium), for her help in statistical analysis N Engl J Med. 1975;293(5):257. doi:10.1056/ (the YEARS study): a prospective, multicentre, and Jérémie Riou, PhD (CHU Angers, UNIV Angers, NEJM197507312930513 Angers, France), for developing the 4PEPS internet 676 JAMA Cardiology June 2021 Volume 6, Number 6 (Reprinted) jamacardiology.com 4-Level Clinical Pretest Probability Score for Suspected Pulmonary Embolism to Safely Decrease Imaging Testing Original Investigation Research 26. DeLong ER, DeLong DM, Clarke-Pearson DL. does not safely exclude pulmonary embolism. pulmonary embolism in the emergency Comparing the areas under two or more correlated J Thromb Haemost. 2011;9(2):300-304. doi:10.1111/ department. Acad Emerg Med. 2014;21(9):949-959. receiver operating characteristic curves: j.1538-7836.2010.04147.x doi:10.1111/acem.12471 a nonparametric approach. Biometrics. 1988;44(3): 30. Kline JA, Hogg MM, Courtney DM, Miller CD, 33. Penaloza A, Verschuren F, Meyer G, et al. 837-845. doi:10.2307/2531595 Jones AE, Smithline HA. D-dimer threshold increase Comparison of the unstructured clinician gestalt, 27. Hutchinson BD, Navin P, Marom EM, Truong with pretest probability unlikely for pulmonary the Wells score, and the revised Geneva score to MT, Bruzzi JF. Overdiagnosis of pulmonary embolism to decrease unnecessary computerized estimate pretest probability for suspected embolism by pulmonary CT angiography. AJRAmJ tomographic pulmonary angiography. 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Hugli O, Righini M, Le Gal G, et al. The pregnant patients investigated for suspected Pulmonary Embolism Rule-out Criteria (PERC) rule jamacardiology.com (Reprinted) JAMA Cardiology June 2021 Volume 6, Number 6 677 Supplemental Online Content Roy P-M, Friou E, Germeau B, et al. Derivation and validation of a 4-level clinical pretest probability score for suspected pulmonary embolism to safely decrease imaging testing. JAMA Cardiol. Published online March 3, 2021. doi:10.1001/jamacardio.2021.0064 eTable. Distribution of 4PEPS among patients and patients with PE in derivation and validation cohorts eFigure. Receiver operating characteristic curves and calibration plots This supplementary material has been provided by the authors to give readers additional information about their work. © 2021 Roy P-M et al. JAMA Cardiology. eTable. Distribution of 4PEPS among patients and patients with PE in derivation and validation cohorts Derivation cohort Internal validation External validation 1 External validation 2 (N=5588) (N=3726) (N=1548) (N=1669) 4PEPS no. with no. with PE no. with no. with No. No. No. No. value PE (%) (%) PE (%) PE (%) 137 2 (1.46) 15 0 (0.00)   3 227 2 (0.88) 34 1 (2.94) 364 5 (1.37) 33 0 (0.00)  2 568 1 (0.18) 104 3 (2.88)  1 660 13 (1.97) 445 9 (2.02) 70 3 (4.29) 209 1 (0.48) 484 18 (3.72) 93 3 (3.23) 0 745 17 (2.28) 265 14 (5.28) 466 18 (3.86) 1 650 26 (4.00) 118 5 (4.24) 215 16 (7.44) 314 18 (5.73) 121 11 (9.09) 2 402 23 (5.72) 136 10 (7.35) 252 26 (10.3) 123 12 (9.76) 3 415 27 (6.51) 128 11 (8.59) 289 26 (9.00) 156 20 (12.8) 4 408 34 (8.33) 103 10 (9.71) 216 27 (12.5) 151 25 (16.6) 5 328 56 (17.1) 116 18 (15.5) 176 39 (22.2) 142 22 (15.5) 6 281 59 (21.0) 65 11 (16.9) 138 37 (26.8) 100 32 (32.0) 7 198 41 (20.8) 73 18 (24.7) 107 38 (35.5) 96 33 (34.4) 8 198 50 (25.3) 45 14 (31.1) 105 46 (43.8) 96 34 (35.4) 9 139 52 (37.4) 56 20 (35.7) 68 27 (39.7) 69 31 (44.9) 10 116 50 (43.1) 45 15 (33.3) 57 29 (50.9) 61 30 (49.2) 11 74 39 (52.7) 30 11 (36.7) 39 21 (53.9) 43 25 (58.1) 12 73 47 (64.4) 20 6 (30.0) 37 25 (67.6) 23 12 (52.2) 13 51 34 (66.7) 8 4 (50.0) 15 10 (66.7) 15 13 (86.7) 14 26 19 (73.1) 7 4 (57.1) 17 11 (64.7) 23 21 (91.3) 15 29 25 (86.2) 10 9 (90.0) © 2021 Roy P-M et al. JAMA Cardiology. eFigure. Receiver operating characteristic curves and calibration plots Receiver operating characteristic curve (Panels 1) and calibration plots (Panels 2) for 4PEPS in the internal validation cohort (Panels A), the first external validation cohort (Panels B) and the second external validation cohort (Panels C). For calibration plots (Panels 2), the grey zone represents the ideal distribution. The distributions of predicted probabilities are shown at the bottom of the graphs. The Hosmer and Lemeshow goodness of fit and Brier score were 0.753 and 0.082, 0.710 and 0.420, and, 0.134 and 0.089, in the internal validation cohort, the first and second external validation cohorts, respectively. © 2021 Roy P-M et al. JAMA Cardiology.

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