Efficacy and Safety of Half Dose Alteplase Added to Heparine, in Patients With Moderate Pulmonary Embolism (MONALYSE)

Efficacy and Safety of Thrombolytic Therapy With Half Dose Alteplase, Added to Standard Anticoagulation Therapy With Heparine, in Patients With Moderate Pulmonary Embolism: a Prospective, Randomized, Open Label,Controlled Trial

The primary aim of this study is to evaluate whether mid dose (safe dose) of Alteplase in addition to standard treatment with heparin (LMWH) in patients with pulmonary embolism (PE) at intermediate risk, it is effective to reduce:

• right ventricular dysfunction
• pulmonary hypertension 24 hours and 7 days after the treatment
• PE recurrence to 7days and 30 days after the treatment without increasing the incidence of bleeding intra-extracranial

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Embolism
• Intervention / Treatment: Drug: Alteplase

Detailed Description

The guidelines of the European Society of Cardiology (ESC2014) confirm the indication for pharmacological revascularization with thrombolysis only to cases of pulmonary embolism at high risk and thus hemodynamically unstable (class of recommendation I, level of evidence B), reserving the surgical or interventional procedures to cases where thrombolysis has failed or is contraindicated, while it remains controversial the role of thrombolysis in patients with pulmonary embolism at intermediate risk; the current state, in EP intermediate risk, the standard treatment involves the administration of low molecular weight heparin (LMWH), or fondaparinux (for 5-10 days followed by anticoagulation therapy with vitamin K antagonists) or alternatively the new anticoagulants oral (NAO). Although the results of the study PEITHO, recently published, confirm the indication for thrombolytic therapy for primary reperfusion in patients with embolism pulmonary high risk and provide element of reflection about the incidence of intracranial hemorrhage major, recent studies suggest that the thrombolysis with tPA to reduced dose (about half the dose that used in standard thrombolysis) in addition to anticoagulants (low molecular weight heparin) may reduce pulmonary hypertension (systolic artery pulmonary pressure> 40 mmHg) and the incidence of recurrent PE. In this protocol, based on the study MOPETT and pharmacokinetic data available, it is used a "safe dose" (safe dose reduced) of alteplase which provides a intravenous (iv) bolus loading dose of 10 mg in 1 min, followed by intravenous infusion 40 mg within two hours (for patients weighing <50 kg loading dose iv bolus of 0.5 mg in 1 min, followed by iv infusion of 40 mg within two hours).

After treatment with alteplase, the heparin therapy will be resumed when aPTT values are less than twice the upper limit of normal; the infusion will be adjusted to maintain aPTT between 50-70 seconds (1.5 to 2.5 times the reference value), and for safety reasons are excluded patients> 65 -70 years (increased risk of bleeding complications related age and comorbidities).

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alberto Conti, MD; Phone Number: 3601095575; Email: aaaconti@hotmail.com
• Study Contact Backup: Name: Lorella Magnani, PharmD; Phone Number: 0585498087; Email: lorella.magnani@usl1.toscana.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. pulmonary embolism at intermediate risk as defined by the Guidelines ESC2014[ documented pulmonary CT angiography]
2. pulmonary hypertension (systolic pulmonary pressure greater or equal to 40 mm Hg) [documented echocardiogram presence of thrombotic material in the right-sided]

3. disfunction Ventricular right confirmed by echocardiogram or TC chest:

   • dilation of the right sections (> 30 mm in parasternal or relationship right ventricle/left ventricle > 1)
   • paradoxical movement of the interventricular septum
   • TAPSE reduced (Tricuspid Annular Plane Systolic Excursion)
   • tricuspid regurgitation with gradient VD/AD> 30 mmHg, in the absence of right ventricular hypertrophy, McConnell sign (apical segment of the free wall of the right ventricle normalKinetic or hyperkinetic than a hypokinesia or akinesia of the remaining parts of the right ventricular wall),

4. myocardial damage confirmed with:

   • Troponin I or T positive
   • higt value of the biomarkers of myocardial damage : BNP or NTproBNP
5. informed consent

Exclusion Criteria:

1. age <18 years and> 65 years
2. HASBLED score ≥ 3 (23)
3. intracranial tumors
4. ischemic stroke within 2 months
5. surgery neurological within 1 month and surgery within 10 days
6. trauma within 15 days
7. hypotension to hospitalization (systemic blood pressure <90 mmHg)
8. uncontrolled hypertension (SBP> 180mmHg and PAD> 110mmHg)
9. clotting disorders
10. thrombocytopenia (<100.000)
11. platelet counts below 100 × 109 /L severe thrombocytopenia (platelet count <50.000 ptl / mm3)
12. liver failure
13. kidney failure
14. gastrointestinal bleeding within 10 days
15. pregnancy or childbirth within 30 days
16. contraindications to the use of thrombolytics
17. contraindications to the use of low molecular weight heparin (enoxaparin)
18. anticoagulation therapy started more than 8 hours
19. COPD
20. endocarditis
21. severe obesity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A; Administered a "safe dose" of Alteplase. All patients are treated with low molecular weight heparin ( LMWH ) according to the Guidelines ESC2014 heparin in addition it is administered a "safe dose" of Alteplase.	Drug: Alteplase; Enoxaparin (1mg) 100UI aXa/kg/sc [LMWH], 15 -30 minutes prior to administration of intravenous (iv) bolus loading dose of 10 mg in 1 min, followed by iv infusion of 40 mg within two hours (for patients weighing <50 kg, a loading dose of bolus of 0.5 mg in 1 min, followed by iv infusion of 40 mg in two hours); the infusion will be adjusted to maintain the value of aPTT between 50-70 seconds (1.5 to 2.5 times the reference value).; Other Names: tPA-tissue Plasminigen Activator
No Intervention: Group B; All patients are treated with low molecular weight heparin ( LMWH ) according to the Guidelines ESC2014 heparin. It not added any treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary hypertension reduction (systolic pulmonary pressure greater or equal to 30 mm Hg)	Pulmonary hypertension reduction documented on echocardiography	24 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of recurrent pulmonary embolism fatal or non fatal	Incidence of recurrent pulmonary embolism fatal or non fatal	7 days
Incidence of hemodynamic shock	Incidence of hemodynamic shock [defined as: need for cardiopulmonary resuscitation, or SBP <90 mmHg for a period ≥15 min or reduction SBP ≥40 mm Hg for SBP ≥15 min, with evidence of systemic hypoperfusion (cold extremities, diuresis <30 mL / h, mental confusion), or need for infusion of amines to maintain adequate organ perfusion and SBP> 90 mm Hg	24 hour and 30 days
Incidence of hospital death from all causes	Incidence of hospital death from all causes	30days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding extracranial minor and major	Bleeding extracranial minor and major	24 hour and 30 days

Collaborators and Investigators

• Sponsor: Azienda U.S.L. 1 di Massa e Carrara
• Investigators: Principal Investigator: Alberto Conti, MD, Azienda USL1 di Massa e Carrara

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: November 11, 2015
• First Submitted That Met QC Criteria: November 12, 2015
• First Posted (Estimated): November 13, 2015

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Pulmonary Embolism at intermediate risk
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: Azienda USL1 Massa e Carrara