Clinical trial NCT05172115: Catheter-Directed Thrombolysis Versus Anticoagulation Monotherapy in Intermediate-High Risk PE
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
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pulmonary Embolism
Pulmonary Thromboembolisms
Embolism, Pulmonary
Right Ventricular Dysfunction
Keywords: Intermediate-high risk pulmonary embolism
Catheter-directed thrombolysis
Anticoagulation
Lead sponsor: Rajaie Cardiovascular Medical and Research Center
Sponsor class: OTHER
First posted: 2021-12-29
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 open-label parallel group randomized controlled trial with concealed allocation sequence and blinded outcome adjudication
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: The proportion of patients with a RV/LV ratio >0.9
timeFrame: At 3 months from randomization
Secondary outcomes:
measure: The proportion of patients with an RV/LV ratio >0.9
timeFrame: At 72 hours from randomization
measure: The proportion of patients with Unrecovered RV
timeFrame: At 3 months from randomization
measure: All-cause mortality
timeFrame: Within 3-month Study period
measure: Major bleeding
timeFrame: Within 3-month Study period
measure: Severe thrombocytopenia
timeFrame: Within 3-month Study period
measure: Vascular access complication
timeFrame: Within 3-month Study period
Other outcomes:
measure: A composite of all-cause death or the primary outcome
timeFrame: Within 3-month Study period
measure: PE-related mortality.
timeFrame: Within 3-month Study period
measure: Hospital length of stay
timeFrame: Within 3-month Study period
measure: Six-minute walk test (6MWt) at three-month follow up
timeFrame: Within 3-month Study period
Locations:
city: Tehran
country: Iran, Islamic Republic of
facility: Rajaie Cardiovascular Medical and Research Center
Study officials:
affiliation: Rajaie Cardiovascular Medical and Research Center
name: Parham Sadeghipour, M.D
role: PRINCIPAL_INVESTIGATOR
References:
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.