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

Pulmonary Embolism Clinical Trial

— CANARY  

Official title:

Catheter-Directed Thrombolysis Versus ANticoagulation Monotherapy in Patients With Acute Intermediate-High Risk PulmonarY Embolism: The CANARY Randomized Clinical Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05172115
• Other study ID #: 97056
• Status: Terminated
• Phase: Phase 3
• Start date: December 22, 2018
• Est. completion date: May 2, 2020

Study information

• Verified date: December 2021
• Source: Rajaie Cardiovascular Medical and Research Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 94
• Est. completion date: May 2, 2020
• Est. primary completion date: February 2, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Embolism
• Embolism, Pulmonary
• Pulmonary Embolism
• Pulmonary Thromboembolisms
• Right Ventricular Dysfunction
• Thromboembolism
• Ventricular Dysfunction
• Ventricular Dysfunction, Right

Intervention

Procedure:
• Conventional catheter-directed thrombolysis (CDT) with recombinant tissue plasminogen activator (rtPA)
Conventional catheter-directed thrombolysis with fixed-dose of 24 mg tissue plasminogen activator infusion over 24 hours

Drug:
• Enoxaparin
Subcutaneous enoxaparin twice-daily (1mg/kg)

Locations

Country	Name	City	State
Iran, Islamic Republic of	Rajaie Cardiovascular Medical and Research Center	Tehran

Sponsors (1)

Lead Sponsor	Collaborator
Rajaie Cardiovascular Medical and Research Center

Country where clinical trial is conducted

Iran, Islamic Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	A composite of all-cause death or the primary outcome	Composite patients who died or patients with a RV/LV ratio >0.9 at a assessed by an imaging core laboratory 3-month follow-up	Within 3-month Study period
Other	PE-related mortality.	Autopsy-confirmed PE with no more likely cause of death or objectively confirmed PE before death in the absence of another more likely cause of death	Within 3-month Study period
Other	Hospital length of stay	The total days of the initial hospitalization	Within 3-month Study period
Other	Six-minute walk test (6MWt) at three-month follow up	The functional capacity of the patient	Within 3-month Study period
Primary	The proportion of patients with a RV/LV ratio >0.9	Proportion of patients with a RV/LV ratio >0.9 at a assessed by an imaging core laboratory 3-month follow-up	At 3 months from randomization
Secondary	The proportion of patients with an RV/LV ratio >0.9	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	At 72 hours from randomization
Secondary	The proportion of patients with Unrecovered RV	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.	At 3 months from randomization
Secondary	All-cause mortality	Survival status of the patient (being alive or dead) at the end of 3 months follow up	Within 3-month Study period
Secondary	Major bleeding	According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)	Within 3-month Study period
Secondary	Severe thrombocytopenia	Platelet count <20.000/µL	Within 3-month Study period
Secondary	Vascular access complication	Major vascular access complication	Within 3-month Study period