Catheter-Directed Thrombolysis Versus Anticoagulation Monotherapy in Intermediate-High Risk PE

Phase 3

Terminated

• Conditions: Right Ventricular Dysfunction; Pulmonary Embolism; Pulmonary Thromboembolisms; Embolism, Pulmonary
• Interventions: Procedure: Conventional catheter-directed thrombolysis (CDT) with recombinant tissue plasminogen activator (rtPA); Drug: Enoxaparin

• Registration Number: NCT05172115
• Lead Sponsor: Rajaie Cardiovascular Medical and Research Center

Brief Summary

In an open-label parallel groups blinded-endpoint randomized clinical trial, the investigators aim to assess the safety and efficacy of conventional catheter-directed thrombolysis (CDT) vs anticoagulation monotherapy on outcomes of patients with acute intermediate-high risk pulmonary embolism. The investigators hypothesize that CDT will have a superior efficacy and safety compared with anticoagulation-only therapy regarding the proportion of patients with a right ventricle to left ventricle (RV/LV) ratio \> 0.9 at a 3-month follow-up by an imaging core laboratory, major bleeding, severe thrombocytopenia, or vascular access complication.

Detailed Description

Treatment of intermediate risk PE is still debated. Despite the promising results of small studies on the efficacy and safety of systemic thrombolytic therapy, larger trials failed to show a net clinical benefit. Pulmonary EmbolIsmTHrOmbolysis (PEITHO) trial which compared the full-dose systemic thrombolysis (i.e., tenecteplase) versus anticoagulation therapy in patients with intermediate-risk PE showed significant lower incidence of mortality or hemodynamic collapse in the first 7 days after randomization in patients who received tenecteplase (2.6% vs 5.6% in placebo group, \[odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P value, 0.02\]). However the mortality benefit was neutralized by the increased risk of major bleeding in thrombolytic arm (11.5% vs 2.4% in the tenecteplase and placebo group, respectively. Importantly, during the long-term follow up (median of 37.8 months) of PEITHO participants, the thrombolytic therapy failed to improve the RV right ventricular function, residual dyspnea ( 36% in thrombolysis group vs 30.1% in the placebo group), or mortality rates (20.3% in thrombolysis group vs 18 % in the placebo group ). CTEPH occurred in ( 2.1% in thrombolysis group vs 3.2% in the placebo group. The lack of benefit of full-dose thrombolytic in PEITHO, might have several explanations. Intermediate risk PE compose of heterogenous group of patients with different prognosis in whom one fits all approach would not be applicable. This heterogeneity in prognosis were underlined in the latest guideline of the European Society of Cardiology (ESC) which classified the intermediate-risk PE category into two groups of intermediate-low and intermediate-high risk patients according to the right ventricle function and cardiac biomarker levels. Second, lower-dose thrombolytic regimen might result in the same benefit with lower bleeding events. CDT, by delivering drug locally, claims to increase the efficacy of thrombolytic agents and consequently decrease the required dose which might translate to lower bleeding events.

In an open-label parallel groups blinded-endpoint randomized clinical trial, we aim to evaluate the safety and efficacy of standard catheter-directed thrombolysis (CDT) vs anticoagulation-only therapy in patients with acute intermediate-high risk pulmonary embolism. The hypothesis is that CDT will have a superior efficacy and safety regarding the proportion of patients with a RV/LV ratio \> 0.9 at a 3-month follow-up assessed by an imaging core laboratory with the lower complications of major bleeding, severe thrombocytopenia, and vascular access complication.

Study Timeline

• Study Start: 2018-12-22
• Primary Completion: 2020-02-02
• Study Completion: 2020-05-02
• Status Verified: 2021-12
• Study First Submitted: 2021-12-10
• Study First Submitted QC: 2021-12-28
• Last Update Submitted: 2021-12-28
• Study First Posted: 2021-12-29
• Last Update Posted: 2021-12-29

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 94

Inclusion Criteria

1. Patients ≥18 years
2. Confirmed acute pulmonary emboli by computed tomography pulmonary angiography (CTPA)
3. Symptom onset ≤14 day
4. Elevated N-terminal-proB-type natriuretic peptide and cardiac troponin
5. Right ventricle/left ventricle ratio >0.9 in transthoracic echocardiography
6. Less than 48 hours of anticoagulation therapy
7. Willingness for participation in the study with signed and dated informed consent form

Exclusion Criteria

1. Pulmonary emboli detected by modalities other than CTPA
2. Segmental PE
3. High risk (massive)
4. Severe renal dysfunction(creatinine clearance [CrCl] below 30 mL/min)
5. Terminal illness Surgery within 2 weeks
6. Platelet count <50.000 /µL
7. Pre and post catheter directed thrombolysis echocardiography exam not possible
8. Contraindication to thrombolytic therapy
9. Concomitant right heart thrombi
10. Allergic reaction to study medications
11. Lack or withdrawal of informed consent

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Conventional catheter-directed thrombolysis (CDT)	Conventional catheter-directed thrombolysis (CDT) with recombinant tissue plasminogen activator (rtPA)	Conventional catheter-directed thrombolysis (CDT) will be the interventional arm. CDT will be administered using fixed-dose of 24 mg tissue plasminogen activator infusion over 24 hours (0.5 mg/h per catheter if bilateral or 1 mg/h per unilateral catheter) with 500 unit per hour of infusion of unfractionated heparin during the thrombolytic therapy. The therapeutic dose of heparin will immediately be substituted the CDT after termination, and twice-daily subcutaneous enoxaparin (1mg/kg) for the first 48 hours after the thrombolytic therapy will be administered. Direct oral anticoagulation will be in ones with no clinical deterioration.
Anticoagulation-only therapy	Enoxaparin	The anticoagulation-only therapy will be the assigned treatment in the control arm. Control patients will receive subcutaneous enoxaparin (twice-daily, 1mg/kg) in the first 48hours of enrollment. Direct oral anticoagulation will be in ones with no clinical deterioration.

Primary Outcome Measures

Name	Time	Method
The proportion of patients with a RV/LV ratio >0.9	At 3 months from randomization	Proportion of patients with a RV/LV ratio \>0.9 at a assessed by an imaging core laboratory 3-month follow-up

Secondary Outcome Measures

Name	Time	Method
The proportion of patients with an RV/LV ratio >0.9	At 72 hours from randomization	A composite of the proportion of patients with a RV/LV ratio \>0.9 at a assessed by an imaging core laboratory 72 hours follow-up
All-cause mortality	Within 3-month Study period	Survival status of the patient (being alive or dead) at the end of 3 months follow up
Major bleeding	Within 3-month Study period	According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
The proportion of patients with Unrecovered RV	At 3 months from randomization	The PEITHO definition for RV recovery was employed, as follows: 1) RV size (at the mid-cavity level In apical 4-chamber view) \<35 mm, 2) pulmonary artery pressure \<35 mm Hg, 3) an RV/LV ratio \<0.9, and 4) the normalization of RV free wall motion. The fulfillment of all the criteria, some criteria, and none of the criteria was defined as complete, partial, and no recovery, respectively.
Severe thrombocytopenia	Within 3-month Study period	Platelet count \<20.000/µL
Vascular access complication	Within 3-month Study period	Major vascular access complication

Trial Locations

Locations (1)

Rajaie Cardiovascular Medical and Research Center; 🇮🇷 Tehran, Iran, Islamic Republic of