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

Primary Purpose

Pulmonary Embolism, Pulmonary Thromboembolisms, Embolism, Pulmonary

Status
Terminated
Phase
Phase 3
Locations
Iran, Islamic Republic of
Study Type
Interventional
Intervention
Conventional catheter-directed thrombolysis (CDT) with recombinant tissue plasminogen activator (rtPA)
Enoxaparin
Sponsored by
Rajaie Cardiovascular Medical and Research Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Embolism focused on measuring Intermediate-high risk pulmonary embolism, Catheter-directed thrombolysis, Anticoagulation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Rajaie Cardiovascular Medical and Research Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Conventional catheter-directed thrombolysis (CDT)

Anticoagulation-only therapy

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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.
All-cause mortality
Survival status of the patient (being alive or dead) at the end of 3 months follow up
Major bleeding
According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
Severe thrombocytopenia
Platelet count <20.000/µL
Vascular access complication
Major vascular access complication

Full Information

First Posted
December 10, 2021
Last Updated
December 28, 2021
Sponsor
Rajaie Cardiovascular Medical and Research Center
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1. Study Identification

Unique Protocol Identification Number
NCT05172115
Brief Title
Catheter-Directed Thrombolysis Versus Anticoagulation Monotherapy in Intermediate-High Risk PE
Acronym
CANARY
Official Title
Catheter-Directed Thrombolysis Versus ANticoagulation Monotherapy in Patients With Acute Intermediate-High Risk PulmonarY Embolism: The CANARY Randomized Clinical Trial
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Terminated
Why Stopped
Due to the COVID-19 pandemic
Study Start Date
December 22, 2018 (Actual)
Primary Completion Date
February 2, 2020 (Actual)
Study Completion Date
May 2, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rajaie Cardiovascular Medical and Research Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Embolism, Pulmonary Thromboembolisms, Embolism, Pulmonary, Right Ventricular Dysfunction
Keywords
Intermediate-high risk pulmonary embolism, Catheter-directed thrombolysis, Anticoagulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
1:1 open-label parallel group randomized controlled trial with concealed allocation sequence and blinded outcome adjudication
Masking
Outcomes Assessor
Masking Description
Allocation sequence concealment and blinded outcome adjudication
Allocation
Randomized
Enrollment
94 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Conventional catheter-directed thrombolysis (CDT)
Arm Type
Experimental
Arm Description
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.
Arm Title
Anticoagulation-only therapy
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Conventional catheter-directed thrombolysis (CDT) with recombinant tissue plasminogen activator (rtPA)
Other Intervention Name(s)
Cragg-McNamara™ valved infusion catheters
Intervention Description
Conventional catheter-directed thrombolysis with fixed-dose of 24 mg tissue plasminogen activator infusion over 24 hours
Intervention Type
Drug
Intervention Name(s)
Enoxaparin
Other Intervention Name(s)
low molecular weight heparin (LMWH)
Intervention Description
Subcutaneous enoxaparin twice-daily (1mg/kg)
Primary Outcome Measure Information:
Title
The proportion of patients with a RV/LV ratio >0.9
Description
Proportion of patients with a RV/LV ratio >0.9 at a assessed by an imaging core laboratory 3-month follow-up
Time Frame
At 3 months from randomization
Secondary Outcome Measure Information:
Title
The proportion of patients with an RV/LV ratio >0.9
Description
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
Time Frame
At 72 hours from randomization
Title
The proportion of patients with Unrecovered RV
Description
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.
Time Frame
At 3 months from randomization
Title
All-cause mortality
Description
Survival status of the patient (being alive or dead) at the end of 3 months follow up
Time Frame
Within 3-month Study period
Title
Major bleeding
Description
According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)
Time Frame
Within 3-month Study period
Title
Severe thrombocytopenia
Description
Platelet count <20.000/µL
Time Frame
Within 3-month Study period
Title
Vascular access complication
Description
Major vascular access complication
Time Frame
Within 3-month Study period
Other Pre-specified Outcome Measures:
Title
A composite of all-cause death or the primary outcome
Description
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
Time Frame
Within 3-month Study period
Title
PE-related mortality.
Description
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
Time Frame
Within 3-month Study period
Title
Hospital length of stay
Description
The total days of the initial hospitalization
Time Frame
Within 3-month Study period
Title
Six-minute walk test (6MWt) at three-month follow up
Description
The functional capacity of the patient
Time Frame
Within 3-month Study period

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients ≥18 years Confirmed acute pulmonary emboli by computed tomography pulmonary angiography (CTPA) Symptom onset ≤14 day Elevated N-terminal-proB-type natriuretic peptide and cardiac troponin Right ventricle/left ventricle ratio >0.9 in transthoracic echocardiography Less than 48 hours of anticoagulation therapy Willingness for participation in the study with signed and dated informed consent form Exclusion Criteria: Pulmonary emboli detected by modalities other than CTPA Segmental PE High risk (massive) Severe renal dysfunction(creatinine clearance [CrCl] below 30 mL/min) Terminal illness Surgery within 2 weeks Platelet count <50.000 /µL Pre and post catheter directed thrombolysis echocardiography exam not possible Contraindication to thrombolytic therapy Concomitant right heart thrombi Allergic reaction to study medications Lack or withdrawal of informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Parham Sadeghipour, M.D
Organizational Affiliation
Rajaie Cardiovascular Medical and Research Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rajaie Cardiovascular Medical and Research Center
City
Tehran
ZIP/Postal Code
1995614331
Country
Iran, Islamic Republic of

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Data will become available to interested investigators upon submitting a reasonable research request, approved by the Steering Committee of the trial.
Citations:
PubMed Identifier
36260302
Citation
Sadeghipour P, Jenab Y, Moosavi J, Hosseini K, Mohebbi B, Hosseinsabet A, Chatterjee S, Pouraliakbar H, Shirani S, Shishehbor MH, Alizadehasl A, Farrashi M, Rezvani MA, Rafiee F, Jalali A, Rashedi S, Shafe O, Giri J, Monreal M, Jimenez D, Lang I, Maleki M, Goldhaber SZ, Krumholz HM, Piazza G, Bikdeli B. Catheter-Directed Thrombolysis vs Anticoagulation in Patients With Acute Intermediate-High-risk Pulmonary Embolism: The CANARY Randomized Clinical Trial. JAMA Cardiol. 2022 Dec 1;7(12):1189-1197. doi: 10.1001/jamacardio.2022.3591.
Results Reference
derived

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

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