Modified Strategy to Safely Rule Out Pulmonary Embolism in the Emergency Department (MODIGLIA-NI)

MOdified DIagnostic strateGy to Safely ruLe-out Pulmonary Embolism In the Emergency depArtment: A Non-Inferiority Cluster Cross-over Randomized Trial

Because a missed PE could be potentially lethal, several researches reported that PE is both overinvestigated and overdiagnosed. The diagnostic gold standard for PE is the computed tomographic pulmonary angiogram (CTPA) and has been shown to have clear risks and other downsides. To limit the use of CTPA, two rules were recently reported to be safe to exclude PE: the PERC rule and the YEARS rule. PERC is an 8 item block of clinical criteria that has recently been validated to safely exclude PE in low risk patients. YEARS is a clinical rule that allow to raise the threshold of D-dimer for the order of CTPA. However, whether a modified diagnostic algorithm that includes these two rules combined could safely reduce imaging study use in the ED is unknown.

This is a non-inferiority, cluster cross-over randomized, international trial.

Each center will be randomized on the sequence of period intervention: 4 months intervention (MOdified Diagnostic Strategy: MODS) followed by 4 months control (usual care), or 4 months control followed by 4 months intervention with 1 month of "wash-out" between the two periods.

All centers will recruit adult emergency patients with a suspicion of PE.

In the control group (usual strategy), patients will be tested for D-dimer, followed if positive by a CTPA.

In the intervention group (MODS) :

All included patients will be tested with quantitative D-dimer. The MODS work-up will be based on YEARS rule :

- If all YEARS criteria are absent, the threshold of D-Dimer for ordering a CTPA will be raised.

If at least one criterion of YEARS is present, then the D-dimer threshold for ordering a CTPA will be as usual.

Study Overview

• Status: Completed
• Conditions: Pulmonary Embolism
• Intervention / Treatment: Other: MODS (MOdified Diagnostic Strategy)

Detailed Description

The diagnosis of Pulmonary Embolism (PE) is a crucial matter in the Emergency Department (ED). Because a missed PE could be potentially lethal, several researches reported that PE is both overinvestigated and overdiagnosed. The diagnostic gold standard for PE is the computed tomographic pulmonary angiogram (CTPA) and has been shown to have clear risks (allergic reaction, acute renal failure, delayed solid tumor) and other downsides such as prolonged ED stay and increased cost. To limit the use of CTPA, two rules were recently reported to be safe to exclude PE: the PERC rule and the YEARS rule.

PERC is an 8 item block of clinical criteria that has recently been validated to safely exclude PE in low risk patients.

YEARS is a clinical rule that allow to raise the threshold of D-dimer for the order of CTPA. However, whether a modified diagnostic algorithm that includes these two rules combined could safely reduce imaging study use in the ED is unknown.

The primary objective of this trial is to assess the safety of a modified diagnostic strategy (MODS) with the YEARS for patients in whom PE was not excluded by PERC score in the ED.

The primary endpoint is the failure percentage of the diagnostic strategy, defined as a diagnosed thrombo-embolic event at 3 month follow-up (either a PE or a deep venous thrombosis), among patients in whom PE has been initially ruled out.

The secondary outcomes try to assess the efficacy of the modified diagnostic strategy (MODS) in reducing order of irradiative imaging studies, ED length of stay, undue onset of anticoagulation regimen, hospital admission, hospital readmission, and mortality at 3 months.

To evaluate the efficacy of the modified diagnostic strategy to reduce overall 3-months total cost.

Secondary endpoints include:

• CTPA or V/Q scan
• Anticoagulant therapy administration
• Length of stay in the ED (hours)
• Admission to the hospital following ED visit.
• All causes re hospitalization at 3 months,
• Death from all causes at 3 months
• Diagnosed pulmonary embolism at 3 month follow-up excluding the isolated sub-segmental pulmonary embolism, among patients in whom PE has been initially ruled out
• PEPS score
• 3 months total cost and cost effectiveness

In the Modified diagnostic strategy (MODS), All included patients will be tested with quantitative D-dimer. The MODS work-up strategy will be based on YEARS rule, that included three criteria (hemoptysis, signs of DVT, PE is the most likely diagnosis)

- If all YEARS criteria are absent, the threshold of D-Dimer for ordering a CTPA will be raised at 1000 ng/ml.

If at least one criterion of YEARS is present, then the D-dimer threshold for ordering a CTPA will be as usual (500 ng/ml, or agex10 for patients aged 50 and over)

Group control :

All included patients will be tested with D-Dimer, the threshold for ordering a CTPA will be as usual (conventional age-adjusted threshold at 500 ng/ml, or agex10 for patients aged 50 and over).

Safely reducing the use of CTPA would be beneficial for the patients, by limiting their risk of associated adverse events and overdiagnosis of PE, and will also reduce their length of stay in the ED, which is associated with better outcomes. Furthermore, reducing supplemental investigations for patients with suspicion of PE may also reduce the cost of ED visits, which would be of great benefit in the context of increasingly resource stretched healthcare services.

• Study Type: Interventional
• Enrollment (Actual): 1414
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Emergency department Hospital Pitié-Salpêtrière
• Spain
  • Barcelona, Spain
    • Emergency department

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient aged ≥ 18 years that presents to an ED
• With new onset of or worsening of shortness of breath or chest pain or syncope

Exclusion Criteria:

• Opposition to the participation to the study
• Anticipated inability to follow up at 3 month
• Other obvious cause than PE for chest pain, syncope or dyspnea
• High clinical probability of PE (estimated by the physician gestalt as > 50%) or low clinical probability and PERC negative patients
• Low clinical probability (estimated by the physician gestalt as < 15%) and no item of the PERC score (heart rate > 100, Sa02 < 95, unilateral leg swelling, hemoptysis, past history of thrombo-embolism, exogen estrogen intake, recent trauma or surgery, age ≥ 50)
• Acute severe presentation (clinical signs of respiratory distress, hypotension, SpO2<90%, shock)
• Concurrent anticoagulation treatment
• Current diagnosed thrombo-embolic event (in the past 6 months)
• Prisoners
• Pregnancy
• No social security
• Participation in another intervention trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Modified strategy MODS; the threshold of D-dimer will depend on the YEARS rule (MODS strategy): If all the three items of YEARS are negative (i.e. No hemoptysis, No clinical sign of deep venous thrombosis and PE is not the most likely diagnosis), then the threshold of D-dimer will be raised at 1000 ng/ml.; If at least one item of YEARS is positive, then the threshold will remain unchanged (">500 ng/ml" for patients aged < 50 and "> agex10" for patients aged 50 and over).A positive result of D-dimer and the absence of other obvious cause for PE will mandate a CTPA, or V/Q scan if CTPA is contra-indicated.A negative result of D-dimer will rule out PE.	Other: MODS (MOdified Diagnostic Strategy); Modified diagnostic strategy (MODS): All included patients will be tested with quantitative D-dimer. The MODS work-up strategy will be based on YEARS rule, that included three criteria (hemoptysis, signs of DVT, PE is the most likely diagnosis) - If all YEARS criteria are absent, the threshold of D-Dimer for ordering a CTPA will be raised at 1000 ng/ml. If at least one criterion of YEARS is present, then the D-dimer threshold for ordering a CTPA will be as usual (500 ng/ml, or agex10 for patients aged 50 and over)
No Intervention: Control group; All included patients will be tested with D-Dimer, threshold for ordering a CTPA as usual

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the failure percentage of the diagnostic strategy, defined as a diagnosed thrombo-embolic event at 3 month follow-up	existence of a diagnosed thrombo embolic event (PE or DVT) among patients in whom PE has been initially ruled out.	3 months follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
reduced irradiative imaging studies	CTPA or V/Q scan	3 months follow up
ED length of stay	length of stay in the ED (hours)	Through ED Discharge within 24 hours
anticoagulant therapy administration	onset of anticoagulant regimen	3 months follow up
hospital admission	admission to the hospital following ED visit	3 months follow up
hospital re admission	all causes re hospitalization at 3 months	3 months
mortality	Death from all causes at 3 months	3 months
Safety of the PEPS score	performance characteristic of the PEPS score for the diagnosis of PE both in the ED and at 3 Months. The false negative rate of PEPS score will be tested, as the theoretical percentage of indicated CTPA according to its value.	3 months
total cost and cost effectiveness	total cost and cost effectiveness (cost per major adverse event averted, namely hospitalisation, rehospitalisation, imaging study, death).	3 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Yonathan Freund, professor, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Freund Y, Chauvin A, Jimenez S, Philippon AL, Curac S, Femy F, Gorlicki J, Chouihed T, Goulet H, Montassier E, Dumont M, Lozano Polo L, Le Borgne P, Khellaf M, Bouzid D, Raynal PA, Abdessaied N, Laribi S, Guenezan J, Ganansia O, Bloom B, Miro O, Cachanado M, Simon T. Effect of a Diagnostic Strategy Using an Elevated and Age-Adjusted D-Dimer Threshold on Thromboembolic Events in Emergency Department Patients With Suspected Pulmonary Embolism: A Randomized Clinical Trial. JAMA. 2021 Dec 7;326(21):2141-2149. doi: 10.1001/jama.2021.20750.
• Philippon AL, Dumont M, Jimenez S, Salhi S, Cachanado M, Durand-Zaleski I, Simon T, Freund Y. MOdified DIagnostic strateGy to safely ruLe-out pulmonary embolism In the emergency depArtment: study protocol for the Non-Inferiority MODIGLIANI cluster cross-over randomized trial. Trials. 2020 Jun 3;21(1):458. doi: 10.1186/s13063-020-04379-y.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Actual): November 20, 2020
• Study Completion (Actual): November 20, 2020

Study Registration Dates

• First Submitted: July 18, 2019
• First Submitted That Met QC Criteria: July 24, 2019
• First Posted (Actual): July 25, 2019

Study Record Updates

• Last Update Posted (Actual): May 3, 2021
• Last Update Submitted That Met QC Criteria: April 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Pulmonary embolism; Emergency department; PERC Rule; Years Rule; Peps Rule
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Embolism and Thrombosis; Emergencies; Embolism; Pulmonary Embolism
• Other Study ID Numbers: APHP180595

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Yes, upon request, after approval by the primary investigator and clinical research platform of East Paris. For the purpose of IPD meta-analysis, or secondary analysis. Unidentifying data will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No