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. 2022 Dec 1;7(12):1189-1197.
doi: 10.1001/jamacardio.2022.3591.

Catheter-Directed Thrombolysis vs Anticoagulation in Patients With Acute Intermediate-High-risk Pulmonary Embolism: The CANARY Randomized Clinical Trial

Parham Sadeghipour  1   2 , Yaser Jenab  3 , Jamal Moosavi  1 , Kaveh Hosseini  3 , Bahram Mohebbi  1   4 , Ali Hosseinsabet  3 , Saurav Chatterjee  5   6 , Hamidreza Pouraliakbar  7 , Shapour Shirani  3 , Mehdi H Shishehbor  8 , Azin Alizadehasl  4 , Melody Farrashi  9 , Mohammad Ali Rezvani  7 , Farnaz Rafiee  7 , Arash Jalali  3 , Sina Rashedi  1   3 , Omid Shafe  1 , Jay Giri  10 , Manuel Monreal  11 , David Jimenez  12   13   14 , Irene Lang  15 , Majid Maleki  1 , Samuel Z Goldhaber  16   17 , Harlan M Krumholz  18   19   20 , Gregory Piazza  16   17 , Behnood Bikdeli  16   17   20   21
Affiliations

Catheter-Directed Thrombolysis vs Anticoagulation in Patients With Acute Intermediate-High-risk Pulmonary Embolism: The CANARY Randomized Clinical Trial

Parham Sadeghipour et al. JAMA Cardiol. .

Abstract

Importance: The optimal treatment of intermediate-high-risk pulmonary embolism (PE) remains unknown.

Objective: To assess the effect of conventional catheter-directed thrombolysis (cCDT) plus anticoagulation vs anticoagulation monotherapy in improving echocardiographic measures of right ventricle (RV) to left ventricle (LV) ratio in acute intermediate-high-risk PE.

Design, setting, and participants: The Catheter-Directed Thrombolysis vs Anticoagulation in Patients with Acute Intermediate-High-Risk Pulmonary Embolism (CANARY) trial was an open-label, randomized clinical trial of patients with intermediate-high-risk PE, conducted in 2 large cardiovascular centers in Tehran, Iran, between December 22, 2018, through February 2, 2020.

Interventions: Patients were randomly assigned to cCDT (alteplase, 0.5 mg/catheter/h for 24 hours) plus heparin vs anticoagulation monotherapy.

Main outcomes and measures: The proportion of patients with a 3-month echocardiographic RV/LV ratio greater than 0.9, assessed by a core laboratory, was the primary outcome. The proportion of patients with an RV/LV ratio greater than 0.9 at 72 hours after randomization and the 3-month all-cause mortality were among secondary outcomes. Major bleeding (Bleeding Academic Research Consortium type 3 or 5) was the main safety outcome. A clinical events committee, masked to the treatment assignment, adjudicated clinical outcomes.

Results: The study was prematurely stopped due to the COVID-19 pandemic after recruiting 94 patients (mean [SD] age, 58.4 [2.5] years; 27 women [29%]), of whom 85 patients completed the 3-month echocardiographic follow-up. Overall, 2 of 46 patients (4.3%) in the cCDT group and 5 of 39 patients (12.8%) in the anticoagulation monotherapy group met the primary outcome (odds ratio [OR], 0.31; 95% CI, 0.06-1.69; P = .24). The median (IQR) 3-month RV/LV ratio was significantly lower with cCDT (0.7 [0.6-0.7]) than with anticoagulation (0.8 [0.7-0.9); P = .01). An RV/LV ratio greater than 0.9 at 72 hours after randomization was observed in fewer patients treated with cCDT (13 of 48 [27.0%]) than anticoagulation (24 of 46 [52.1%]; OR, 0.34; 95% CI, 0.14-0.80; P = .01). Fewer patients assigned to cCDT experienced a 3-month composite of death or RV/LV greater than 0.9 (2 of 48 [4.3%] vs 8 of 46 [17.3%]; OR, 0.20; 95% CI, 0.04-1.03; P = .048). One case of nonfatal major gastrointestinal bleeding occurred in the cCDT group.

Conclusions and relevance: This prematurely terminated randomized clinical trial of patients with intermediate-high-risk PE was hypothesis-generating for improvement in some efficacy outcomes and acceptable rate of major bleeding for cCDT compared with anticoagulation monotherapy and provided support for a definitive clinical outcomes trial.

Trial registration: ClinicalTrials.gov Identifier: NCT05172115.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shishehbor reported receiving grants from Inari; personal fees from Boston Scientific, Abbott VAscular, Philips, and Terumo; and equity from Advanced Nano Therapies and Inquis Medical outside the submitted work. Dr Giri reported receiving personal fees from Inari, Boston Scientific, and Abiomed and grants from Inari, Boston Scientific, Abiomed, and the National Heart, Lung, and Blood Institute outside the submitted work. Dr Monreal reported receiving personal fees from Sanofi and grants from Sanofi, Rovi Pharmaceuticals, and Leo Pharma outside the submitted work. Dr Jimenez reported receiving personal fees from Bristol Myers Squibb, Pfizer, Sanofi, Leo Pharma, and Rovi Pharmaceuticals and grants from Daiichi-Sankyo, outside the submitted work; Dr Jimenez reported being a member of the steering committee of Pulmonary Embolism International Thrombolysis Study 3 (PEITHO-3) trial. Dr Lang reported receiving grants from Janssen and AOPHealth during the conduct of the study and personal fees from Janssen, AOPHealth, MSD Pharma Services, and Sanofi outside the submitted work. Dr Goldhaber reported receiving grants from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, Daiichi-Sankyo, Janssen, the National Heart, Lung, and Blood Institute, the Thrombosis Research Institute, and Pfizer, and consulting fees Bayer, Agile, Boston Scientific, Boehringer Ingelheim, and Pfizer outside the submitted work. Dr Krumholz reported receiving personal fees from UnitedHealth, IBM, Watson Health, Aetna, Facebook, Element Science, Aetna, Reality Labs, F-Prime, Tesseract/4Catalyst, Martin/Baughman Law Firm, Arnold and Porter Law Firm, Siegfried and Jensen Law Firm, the National Center for Cardiovascular Diseases, Beijing, China, and the Massachusetts Medical Society (as coeditor of Journal Watch Cardiology); being a cofounder of HugoHealth, Refactor Health; having contracts with the US Centers for Medicare & Medicaid Services Association; grants from Medtronic, the US Food and Drug Administration, Johnson & Johnson, Bristol Myers Squibb/Pfizer, Janssen, Boston Scientific, Bayer, Alexion, Amgen, and the Shenzhen Center for Health Information; and consulting fees from Amgen, BSC, Janssen, Bristol Myers Squibb/Pfizer outside the submitted work. Dr Bikdeli reported receiving research support from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, a Career Development Award by the American Heart Association, and VIVA Physicians; and being a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of inferior vena cava filters. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Enrollment and Randomization
aAmong 169 patients not meeting the eligibility criteria, 91, 48, and 11 patients were categorized as having low, intermediate-low, and high risk of developing pulmonary emboli. Ten patients had 1 or more contraindication to fibrinolytic therapy. Eight patients experienced end-stage kidney disease. One patient had allergy to iodine-based contrast. bSix patients in the study (2 in the conventional catheter-directed thrombolysis group and 4 in the anticoagulation group) did not agree to participate in the 3-month on-site imaging follow-up, but they did agree to have off-site clinical follow-up assessment by phone interview. cAll images obtained from patients participating in the echocardiographic 3-month follow-up were considered acceptable by the core laboratory.
Figure 2.
Figure 2.. Subgroup Analysis for the Primary Outcome
BMI indicates body mass index; CAD, coronary artery disease; CDT, catheter-directed thrombolysis; NR, not reported; RR, risk ratio. aBMI calculated as weight in kilograms divided by height in meters squared.
See this image and copyright information in PMC

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