CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the CANARY Trial

Table of contents for the CANARY Trial summary:

• Visual abstract
• Summary
• References
• Credits
• Twitter Archive

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

October 19, 2022

Authors: Parham Sadeghipour, Yaser Jenab, Jamal Moosavi, Kaveh Hosseini, Bahram Mohebbi, Ali Hosseinsabet, Saurav Chatterjee, Hamidreza Pouraliakbar, Shapour Shirani, Mehdi H Shishehbor, Azin Alizadehasl, Melody Farrashi, Mohammad Ali Rezvani, Farnaz Rafiee, Arash Jalali, Sina Rashedi, Omid Shafe, Jay Giri, Manuel Monreal, David Jimenez, Irene Lang, Majid Maleki, Samuel Z Goldhaber, Harlan M Krumholz, Gregory Piazza, Behnood Bikdeli

Link to Manuscript: https://jamanetwork.com/journals/jamacardiology/article-abstract/2797198

Relevant Literature – CANARY Trial

• The role of reperfusion therapy (also known as “escalation of care”) for the treatment of intermediate-high risk pulmonary embolism (PE) is not well established.
• Catheter-directed thrombolysis (CDT) refers to the administration of a thrombolytic drug directly into the pulmonary arterial circulation, generally over 24-48 hours, with a maximal dosage of thrombolytic. This is different from systemic thrombolysis, which involves the peripheral intravenous administration of thrombolytics, with higher doses of medication over a shorter period of time. The thrombolytics currently used are alteplase, tenecteplase, reteplase, urokinase, and streptokinase.
• In patients with submassive or intermediate-risk PE (defined as patients without acute hypotension but with biologic and/or imaging evidence of acute right ventricular dysfunction), systemic thrombolysis has been shown to improve hemodynamic outcomes, but is associated with an elevated risk of intra- and extracranial hemorrhage.¹
• The goal of CDT is to achieve reperfusion similar to systemic thrombolysis, while decreasing the rate of major and intracranial bleeding, by delivering a localized, lower thrombolytic dose.¹
• CDT has been proven to have favorable hemodynamic outcomes and lower bleeding complications in patients with submassive/intermediate-high risk PE. There are currently no data to support short-term mortality benefits with catheter-based approaches for the treatment of PE.³
• Prior trials evaluating CDT in the treatment of acute PE have focused on imaging surrogates for improved short-term outcomes, such as RV:LV ratio. There is uncertainty regarding the long-term improvement of RV function after treatment with CDT compared with systemic thromboloysis or anticoagulation monotherapy.¹

Relevant Guidelines – CANARY Trial

• European Society of Cardiology Guidelines (2019)⁶
  • Surgical embolectomy or CDT should be considered for patients with hemodynamic deterioration on anticoagulation treatment (Class IIa, level C)
  • Percutaneous CDT should be considered for patients with high-risk PE, in whom thrombolysis is contraindicated or has failed (Class IIa, level C)
• American Heart Association Scientific Statement (2019)¹
  • If patients deteriorate (hemodynamic, respiratory, or RV function), more intensive therapies, including thrombolysis, catheter-based or surgical embolectomy, and mechanical circulatory support, should be strongly considered.
  • Among those who remain hemodynamically stable, a careful assessment for factors that elevate the risk of decompensation should be undertaken, including elevated pulmonary embolism severity index (PESI) or simplified PESI score, severe PE-related functional impairment, and objective signs of severely diminished end-organ perfusion or stroke volume. In those who meet these criteria and have non-prohibitive bleeding risk, systemic thrombolysis or CDT may be considered to improve RV performance immediately.

Study Rationale – CANARY Trial

• There is limited evidence regarding durable effects on improving RV function with CDT compared with anticoagulation monotherapy in patients with acute intermediate-high-risk PE.

Objective – CANARY Trial

The CANARY trial aimed to compare the effect of CDT plus anticoagulation to anticoagulation monotherapy on biologic and echocardiographic measures of RV strain (serum NT-pro-BNP, serum troponin, RV/LV ratio) in acute intermediate-high–risk PE.

Trial: – CANARY Trial

• Open-label, parallel-group, masked-end point, and randomized
• Performed in two cardiovascular centers in Tehran, Iran

Intervention

• Therapy with unfractionated heparin was started in all potentially eligible patients prior to randomization
• Patients were randomized to anticoagulation monotherapy or CDT:

Anticoagulation monotherapy

• Twice-daily subcutaneous enoxaparin (1 mg/kg) for the first 48 hours after enrollment
• Subsequent transition to oral anticoagulant was left to the discretion of treating physicians

CDT

• Transfer to the catheterization laboratory within 60 minutes of randomization
• Catheter(s) placed via femoral artery: one catheter for unilateral and two catheters for bilateral PE
• Infusion of alteplase at 0.5 mg/h per catheter plus a fixed dose of unfractionated heparin at 500 U/h
• Transition to twice-daily enoxaparin (1 mg/kg) for the first 48 hours after completion of fibrinolytic therapy in patients without procedural complications or hemodynamic instability
• Subsequent transition to oral anticoagulant was left to the discretion of treating physicians

Enrollment Criteria

Inclusion criteria

• Age ≥ 18 years old with acute intermediate-high risk PE confirmed by CTPA and symptoms onset ≤ 14 days
• NT-proBNP ≥ 600 pg/mL and high-sensitivity troponin T ≥ 14 pg/mL for patients aged < 75 years and ≥ 45 pg/mL for those ≥ 75 years
• RV/LV ratio >0.9 in CTPA
• Simplified PESI ≥ 1
• Randomized within 48 hours since initiation of anticoagulation therapy
• Not enrolled in another blinded randomized trial
• Willing to participate and consent

Exclusion criteria

• Pulmonary emboli diagnosed with modalities other than CTPA
• Pulmonary emboli limited to segmental and sub-segmental branches of pulmonary arteries
• High-risk or massive PE
• Severe renal dysfunction with CrCl < 30 mL/min
• Terminal illness, as assessed by treating clinicians
• Surgery within the prior 2 weeks
• Platelet count < 50,000/ìL
• Any absolute contraindication for fibrinolytic therapy: active internal bleeding, history of intracranial hemorrhage, ischemic stroke within the past 3-months, cerebral aneurysm, primary or metastatic intracranial malignancy, presence of signs or symptoms of acute aortic dissection, or major trauma or head injury in the prior 3-weeks
• Evidence of right heart thrombi
• Allergic reaction to study medications
• Lack of withdrawal of informed consent

Outcomes

• Primary
  • The proportion of patients with RV/LV ratio > 0.9 at 3 months 
• Secondary
  • The proportion of patients with RV/LV ratio > 0.9 at 72 hours after randomization
  • The proportion of patients with unrecovered RV at 3-months
  • All-cause mortality at 3-months

Statistical Analysis

• A sample size of 144 patients in each group (288 total) would be needed to reach a power of 80%
• Categorical variables were analyzed using Chi-square or Fisher exact test
• Continuous variables were analyzed with T-test
• After completion of enrollment but before analyzing the trial data, it was planned to conduct a random-effect meta-analysis from CDT arms of prior randomized trials (ULTIMA, OPTALYSE-PE, SUNSET-PE) plus the current trial, to assess the pooled relative frequency of bleeding events

Note: Due to the COVID-19 pandemic and its strain on the healthcare system, it was decided to stop recruitment in February 2020. The 3-month outcomes were analyzed in patients with valid values. Other outcomes were analyzed on all randomly assigned patients.

Participant Characteristics:

Outcomes

• Proportion of patients with RV/LV ratio > 0.9 at 3-month follow-up: 4.3% vs. 12.8%; OR 0.31 (CI 0.06-1.69; P=0.24)

Secondary Outcomes

• Proportion of patients with RV/LV ratio > 0.9 at 72 hours: 27.0% vs. 52.1%; OR 0.34 (CI 0.14-0.80; P=0.01)
• Proportion of patients with unrecovered RV function at 3-month follow-up: 6.2% vs. 28.2%; OR 0.18 (CI 0.06-0.77; P=0.009)
• All-cause mortality at 3-months: 0% vs. 6.5%; OR -6.50 (-13.06-6.14, P=0.40)

Safety Outcomes

• 1 case of Bleeding Academic Research Consortium (BARC) type 3a major bleeding (nonfatal GI bleed) occurred in the CDT group
• No fatal or intracranial bleeding occurred in either group
• 3 cases of minor bleeding (vascular access-site hematoma, BARC type 2) occurred in the CDT group

Adverse Events

Pooled frequency of bleeding events (including ULTIMA, OPTALYSE-PE, SUNSET-PE, and CANARY trials)

• Fatal bleeding: 0.02% (95% CI, 0-1.15%)
• Intracranial hemorrhage: 0.44% (95% CI, 0-2.17%)
• Major bleeding: 1.76% (95% CI, 0.20%-4.27%)

Conclusions

• There was no statistically significant difference in the proportion of patients with RV/LV ratios > 0.9 in the CDT group vs. anticoagulation monotherapy group, at 3 months follow up. However, CDT was associated with a statistically significant decrease in the proportion of patients with RV/LV ratio > 0.9 at 72 hours after randomization.
• CDT was also associated with more echocardiographic RV recovery at 3-month follow-up, when compared to anticoagulation monotherapy.

Limitations & Considerations

• The main limitation of the CANARY trial was stopping enrollment prematurely due to the COVID-19 pandemic, resulting in recruiting a total of 94 patients, and leading to an underpowered trial.
• Women were underrepresented in the trial, accounting for only 29% of the patient sample.
• Majority of the sample had a low baseline bleeding risk profile, which may represent selection bias.
• Due to logistical limitations, the 6-minute walk test at 3-month follow-up was only performed in one enrolling center.

1. Giri J, Sista AK, Weinberg I, et al. Interventional Therapies for Acute Pulmonary Embolism: Current Status and Principles for the Development of Novel Evidence: A Scientific Statement From the American Heart Association. Circulation. 2019;140(20):E774-E801. doi:10.1161/CIR.0000000000000707
2. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi:10.1056/NEJMOA1302097
3. Pei DT, Liu J, Yaqoob M, et al. Meta-Analysis of Catheter Directed Ultrasound-Assisted Thrombolysis in Pulmonary Embolism. Am J Cardiol. 2019;124(9):1470-1477. doi:10.1016/J.AMJCARD.2019.07.040
4. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479-486. doi:10.1161/CIRCULATIONAHA.113.005544
5. Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015;8(10):1382-1392. doi:10.1016/J.JCIN.2015.04.020
6. Konstantinides S V., Meyer G, Bueno H, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543-603. doi:10.1093/EURHEARTJ/EHZ405

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