Clinical trial NCT02268903: Diuretic Versus Placebo in Pulmonary Embolism
Official title: Diuretic Versus Placebo in Pulmonary Embolism With Right Ventricular Enlargement: a Double-blind Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Pulmonary Embolism With Right Ventricle Enlargement
Keywords: Pulmonary Embolism
Right Ventricle failure
Diuretics
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2014-10-20
Enrollment: 270
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Pulmonary Embolism (PE) is a frequent and severe disease with an annual incidence of about 75000 cases in France and a short-term mortality rate of about 10%. Death is usually related to an acute right ventricular (RV) failure due to the increase in right ventricular afterload. Treatment of PE with RV failure consists in fluid expansion and thrombolysis in case of shock. However several studies suggest that fluid expansion may worsen acute RV failure by increasing RV dilatation and ischemia and left ventricular compression by RV dilatation. Thus, current guidelines regarding PE treatment remain unclear about the use of fluid expansion. In a preliminary study published by our group, we showed that diuretic treatment in the setting of PE with RV dilatation is safe and is associated with an increase in urine output, a decrease in heart rate and an increase in SpO2 in normotensive patients with oliguria. This may be related to the decrease of ventricular interdependence and enhancement of both LV and RV function.

The main objective of the study is to evaluate the 24-hours clinical benefit of furosemide in patients referred for acute PE with RV dilatation compared to placebo. The combination of urine output and sPESI clinical parameters reflects hemodynamic status. It is relevant as it indicates the disappearance of pre-shock symptoms and is therefore associated with a lower event risk. Thus, it allows early discharge of the patients from the intensive care unit.


Eligibility criteria: Inclusion Criteria:

Patients aged 18 years and over with

1. Symptomatic acute pulmonary embolism with first clinical symptoms within 15 days, and objectively confirmed by CT scan
2. RV dysfunction (≥1 criterion) confirmed by elevated BNP value or echocardiography or spiral computed tomography of the chest:

   * Echocardiography

     o Right/Left ventricular end diastolic diameter \> 1(apical or subcostal 4-chamber view)
   * Computed tomography

     o Right/Left short-axis diameter ratio\>0.9 (transverse plane)
   * Positive Nt-proBNP (\>600) or BNP\>200 pg/mL
3. One abnormal following PESI criteria

   * Heart Rate\>110/min
   * Systolic blood pressure\<100mmHg
   * Arterial oxyhemoglobin level\<90% on room air or after 5 minutes of oxygen withdrawal.

Exclusion Criteria:

* Cardiogenic shock requiring thrombolysis
* Previous significant left ventricular insufficiency (LVEF\<45%)
* Systolic blood pressure\<90mmHg at admission
* Age ≤ 18 years
* Pregnancy
* No health insurance
* Patients deprived of liberty or under legal protection
* Creatinin clearance \<30mL/min/m²
* hypersensibility to furosemide or its excipients
* functional renal insufficiency
* Hepatic encephalopathy
* Urinary tracks obstruction
* Hypovolemia or dehydration.
* Sever hypokalemia (K+ \< 3mmol/L)
* Severe hyponatremia (Na+ \< 125mmol/L)
* Ongoing hepatitis and hepatic insufficiency severe in patients with renal insufficiency or dialysis

Primary outcomes:
measure: Primary end point will be a combined clinical criterion, to reach the primary endpoint, patients have to meet all the following criteria: - Urine output> 0.5ml/kg/h - Normalization of clinical parameters of simplified PESI score
timeFrame: 24 hours
Secondary outcomes:
measure: patients have to meet all the four following criteria: - Urine output> 0.5ml/kg/h over 24 hours - Normalization of clinical parameters of simplified PESI score - Urine output
timeFrame: 48 hours
measure: - Composite criteria including death, need for catecholamine, cardiac arrest and mechanical ventilation during hospitalization and at 1 month from inclusion - NYHA score
timeFrame: In hospital and 1 month
measure: o RV/LV ratio and decrease from baseline o Systolic pulmonary pressure and decrease from baseline o Tricuspid annular plane systolic expansion (TAPSE) at o Tricuspid annular plane systolic expansion (TAPSE) variation from baseline
timeFrame: 24 hours abd 1 month
measure: - NT-proBNP or BNP decrease at 24hours - Creatinin and liver enzymes variations at 24hours
timeFrame: 24 hours
Other outcomes:
Locations:
city: Creteil
country: France
facility: Henri Mondor Hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Luc DUBOIS-RANDE, PU-PH
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Lee FA. Hemodynamics of the right ventricle in normal and disease states. Cardiol Clin. 1992 Feb;10(1):59-67.
citation: Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP; ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008 Sep;29(18):2276-315. doi: 10.1093/eurheartj/ehn310. Epub 2008 Aug 30.
citation: Perlroth DJ, Sanders GD, Gould MK. Effectiveness and cost-effectiveness of thrombolysis in submassive pulmonary embolism. Arch Intern Med. 2007 Jan 8;167(1):74-80. doi: 10.1001/archinte.167.1.74.
citation: Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993 Feb 27;341(8844):507-11. doi: 10.1016/0140-6736(93)90274-k.
citation: Lim P, Delmas C, Sanchez O, Meneveau N, Rosario R, Bouvaist H, Bernard A, Mansourati J, Couturaud F, Sebbane M, Coste P, Rohel G, Tardy B, Biendel C, Lairez O, Ivanes F, Gallet R, Dubois-Rande JL, Fard D, Chatelier G, Simon T, Paul M, Natella PA, Layese R, Bastuji-Garin S. Diuretic vs. placebo in intermediate-risk acute pulmonary embolism: a randomized clinical trial. Eur Heart J Acute Cardiovasc Care. 2022 Jan 12;11(1):2-9. doi: 10.1093/ehjacc/zuab082.
citation: Gallet R, Meyer G, Ternacle J, Biendel C, Brunet A, Meneveau N, Rosario R, Couturaud F, Sebbane M, Lamblin N, Bouvaist H, Coste P, Maitre B, Bastuji-Garin S, Dubois-Rande JL, Lim P. Diuretic versus placebo in normotensive acute pulmonary embolism with right ventricular enlargement and injury: a double-blind randomised placebo controlled study. Protocol of the DiPER study. BMJ Open. 2015 May 22;5(5):e007466. doi: 10.1136/bmjopen-2014-007466.