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

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

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of, 1995614331
    • Rajaie Cardiovascular Medical and Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Conventional catheter-directed thrombolysis (CDT); 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.	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; Other Names: Cragg-McNamara™ valved infusion catheters
ACTIVE_COMPARATOR: Anticoagulation-only therapy; 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.	Drug: Enoxaparin; Subcutaneous enoxaparin twice-daily (1mg/kg); Other Names: low molecular weight heparin (LMWH)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
Major bleeding	According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding)	Within 3-month Study period
Severe thrombocytopenia	Platelet count <20.000/µL	Within 3-month Study period
Vascular access complication	Major vascular access complication	Within 3-month Study period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
Hospital length of stay	The total days of the initial hospitalization	Within 3-month Study period
Six-minute walk test (6MWt) at three-month follow up	The functional capacity of the patient	Within 3-month Study period

Collaborators and Investigators

• Sponsor: Rajaie Cardiovascular Medical and Research Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 22, 2018
• Primary Completion (ACTUAL): February 2, 2020
• Study Completion (ACTUAL): May 2, 2020

Study Registration Dates

• First Submitted: December 10, 2021
• First Submitted That Met QC Criteria: December 28, 2021
• First Posted (ACTUAL): December 29, 2021

Study Record Updates

• Last Update Posted (ACTUAL): December 29, 2021
• Last Update Submitted That Met QC Criteria: December 28, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Anticoagulation; Intermediate-high risk pulmonary embolism; Catheter-directed thrombolysis
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thromboembolism; Pulmonary Embolism; Ventricular Dysfunction; Ventricular Dysfunction, Right; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Tissue Plasminogen Activator; Plasminogen
• Other Study ID Numbers: 97056

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will become available to interested investigators upon submitting a reasonable research request, approved by the Steering Committee of the trial.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No