Expanding a peptide-covalent probe hybrid for PET imaging of S. aureus driven focal infections.

BACKGROUND: The urgent demand for innovative theranostic strategies to combat bacterial resistance to antibiotics is evident, with substantial implications for global health. Rapid diagnosis of life-threatening infections can expedite treatment, improving patient outcomes. Leveraging diagnostic modalities i.e., positron emission tomography (PET) and single photon emission computed tomography (SPECT) for detecting focal infections has yielded promising results. Augmenting the sensitivity of current PET and SPECT tracers could enable effective imaging of pathogenic bacteria, including drug-resistant strains.UBI (29-41), an antimicrobial peptide (AMP) fragment recognizes the S. aureus membrane through electrostatic binding. Radiolabeled UBI (29-41) is a promising SPECT and PET-based tracer for detecting focal infections. 2-APBA (2-acetyl-phenyl-boronic acid), a non-natural amino acid, specifically targets lysyl-phosphatidyl-glycerol (lysyl-PG) on the S. aureus membranes, particularly in AMP-resistant strains. We propose that combining UBI with 2-APBA could enhance the diagnostic potential of radiolabeled UBI. RESULTS: Present work aimed to compare the diagnostic potential of two radiolabeled peptides, namely UBI (29-41) and 2-APBA modified UBI (29-41), referred to as UBI and UBI-APBA. APBA modification imparted antibacterial activity to the initially non-bactericidal UBI against S. aureus by inducing a loss of membrane potential. The antibacterial activity demonstrated by UBI-APBA can be ascribed to the synergistic interaction of both UBI and UBI-APBA on the bacterial membrane. To enable PET imaging, we attached the chelator 1,4,7-triazacyclononane 1-glutaric acid 4,7-acetic acid (NODAGA) to the peptides for complexation with the positron emitter Gallium-68 (68Ga). Both NODAGA conjugates were radiolabeled with 68Ga with high radiochemical purity. The resultant 68Ga complexes were stable in phosphate-buffered saline and human serum. Uptake of these complexes was observed in S. aureus but not in mice splenocytes, indicating the selective nature of their interaction. Additionally, the APBA conjugate exhibited superior uptake in S. aureus while preserving the selectivity of the parent peptide. Furthermore, [68Ga]Ga-UBI-APBA demonstrated accumulation at the site of infection in rats, with an improved target-to-non-target ratio, as evidenced by ex-vivo biodistribution and PET imaging. CONCLUSIONS: Our findings suggest that linking UBI, as well as AMPs in general, with APBA shows promise as a strategy to augment the theranostic potential of these molecules.

Long-term all-cause death prediction by coronary, aortic, and valvular calcification in patients with acute ST-segment elevation myocardial infarction.

BACKGROUND: To determine the prognostic value of cumulative calcification score of coronary artery calcification (CAC), thoracic aortic calcification (TAC) and aortic valve calcification (AVC) in acute ST segment elevation myocardial infarction (STEMI) patients. METHODS: This was a retrospective, single-center cohort study. A total of 332 STEMI patients who received primary percutaneous coronary intervention (PPCI) were enrolled in this study between January 2010 to October 2018. We assessed the calcification in the left anterior descending branch (LAD), left circumflex branch (LCX), right coronary artery (RCA), thoracic aorta, and aortic valve. Calcification of each part was counted as 1 point, and the cumulative calcification score was calculated as the sum of all points. The primary endpoint was all-cause mortality. Multivariate Cox proportional hazards models were used to determine association of cumulative calcification score with end points. The performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis and absolute net reclassification improvement (NRI), compared with the Global Registry of Acute Coronary Events (GRACE) risk score. RESULTS: The overall population's calcification score was 2.0 ± 1.6. During a mean follow-up time of 69.8 ± 29.3 months, the all-cause mortality rate was 12.1%. Kaplan-Meier curve showed that the score was significantly associated with mortality (log-rank p < 0.001). The multivariable Cox proportional hazard analyses showed that a calcification score of 4-5 was independently associated with all-cause death in STEMI patients [hazard ratio (HR) = 2.32, 95% confidence interval (CI): 1.01-5.31, p = 0.046]. The area under the ROC curve (AUC) of the calcification score was 0.67 (95% CI: 0.61-0.72), and the AUC of the GRACE score was 0.80 (95% CI: 0.75-0.84). There was no statistical difference in the predictive value between both scores for 3-year mortality in STEMI patients after PPCI (p = 0.06). Based on the NRI analysis, the calcification score showed better risk classification compared with the GRACE score (absolute NRI = 6.63%, P = 0.027). CONCLUSION: The cumulative calcification score is independently associated with the long-term prognosis of STEMI patients after PPCI.

Private Equity and Cardiovascular Health Care.

This Viewpoint discusses involvement of private equity firms in health care.

De-escalation of dual antiplatelet therapy for patients with acute coronary syndrome after percutaneous coronary intervention: a systematic review and network meta-analysis.

OBJECTIVES: To compare dual antiplatelet therapy (DAPT) de-escalation with five alternative DAPT strategies in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). DESIGN: We conducted a systematic review and network meta-analysis (NMA). Parallel-arm randomised controlled trials (RCTs) comparing DAPT strategies were included and arms of interest were compared via NMA. Partial ranking of each identified arm and for each investigated endpoint was also performed. SETTING AND PARTICIPANTS: Adult patients with ACS (≥18 years) undergoing PCI with indications for DAPT. SEARCH METHODS: A comprehensive search covered several databases (PubMed, Embase, Cochrane Central, MEDLINE, Conference Proceeding Citation Index-Science) from inception to 15 October 2023. Medical subject headings and keywords related to ACS, PCI and DAPT interventions were used. Reference lists of included studies were screened. Clinical trials registers were searched for ongoing or unpublished trials. INTERVENTIONS: Six strategies were assessed: T1 arm: acetylsalicylic acid (ASA) and prasugrel for 12 months; T2 arm: ASA and low-dose prasugrel for 12 months; T3 arm: ASA and ticagrelor for 12 months; T4 arm: DAPT de-escalation (ASA+P2Y12 inhibitor for 1-3 months, then single antiplatelet therapy with potent P2Y12 inhibitor or DAPT with clopidogrel); T5 arm: ASA and clopidogrel for 12 months; T6 arm: ASA and clopidogrel for 3-6 months. MAIN OUTCOME MEASURES: Primary outcome: Cardiovascular mortality. SECONDARY OUTCOMES: bleeding events (all, major, minor), stent thrombosis (ST), stroke, myocardial infarction (MI), all-cause mortality, major adverse cardiovascular events (MACE). RESULTS: 23 RCTs (75 064 patients with ACS) were included. No differences in cardiovascular mortality, all-cause death, recurrent MI or MACE were found when the six strategies were compared, although with different levels of certainty of evidence. ASA and clopidogrel for 12 or 3-6 months may result in a large increase of ST risk versus ASA plus full-dose prasugrel (OR 2.00, 95% CI 1.14 to 3.12, and OR 3.42, 95% CI 1.33 to 7.26, respectively; low certainty evidence for both comparisons). DAPT de-escalation probably results in a reduced risk of all bleedings compared with ASA plus full-dose 12-month prasugrel (OR 0.49, 95% CI 0.26 to 0.81, moderate-certainty evidence) and ASA plus 12-month ticagrelor (OR 0.52, 95% CI 0.33 to 0.75), while it may not increase the risk of ST. ASA plus 12-month clopidogrel may reduce all bleedings versus ASA plus full-dose 12-month prasugrel (OR 0.66, 95% CI 0.42 to 0.94, low certainty) and ASA plus 12-month ticagrelor (OR 0.70, 95% CI 0.52 to 0.89). CONCLUSIONS: DAPT de-escalation and ASA-clopidogrel regimens may reduce bleeding events compared with 12 months ASA and potent P2Y12 inhibitors. 3-6 months or 12-month aspirin-clopidogrel may increase ST risk compared with 12-month aspirin plus potent P2Y12 inhibitors, while DAPT de-escalation probably does not.

Developmental or Procedural Vena Cava Interruption and Venous Thromboembolism: A Review.

The inferior vena cava (IVC) and superior vena cava are the main conduits of the systemic venous circulation into the right atrium. Developmental or procedural interruptions of vena cava might predispose to stasis and deep vein thrombosis (DVT) distal to the anomaly and may impact the subsequent rate of pulmonary embolism (PE). This study aimed to review the various etiologies of developmental or procedural vena cava interruption and their impact on venous thromboembolism. A systematic search was performed in PubMed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines per each clinical question. For management questions with no high-quality evidence and no mutual agreements between authors, Delphi methods were used. IVC agenesis is the most common form of congenital vena cava interruption, is associated with an increased risk of DVT, and should be suspected in young patients with unexpected extensive bilateral DVT. Surgical techniques for vena cava interruption (ligation, clipping, and plication) to prevent PE have been largely abandoned due to short-term procedural risks and long-term complications, although survivors of prior procedures are occasionally encountered. Vena cava filters are now the most commonly used method of procedural interruption, frequently placed in the infrarenal IVC. The most agreed-upon indication for vena cava filters is for patients with acute venous thromboembolism and coexisting contraindications to anticoagulation. Familiarity with different forms of vena cava interruption and their local and systemic adverse effects is important to minimize complications and thrombotic events.

Capturing Sialyl-glycan on Live Cancer Cells by Tailored Boronopeptide.

Boronic acid-containing molecules are substantially popularized in chemical biology and medicinal chemistry due to the broad spectrum of covalent conjugations as well as interaction modules offered by the versatile boron atom. Apparently, the WGA peptide (wheat germ agglutinin, 62-73), which shows a considerably low binding affinity to sialic acid, turned into a selective and >5 folds potent binder with the aid of a suitable boronic acid probe installed chemoselectively. In silico studies prompted us to install BA probes on the cysteine residue, supposedly located in close proximity to the bound sialic acid. In vitro studies revealed that the tailored boronopeptides show enhanced binding ability due to the synergistic recognition governed by selective non-covalent interactions and cis-diol boronic acid conjugation. The intense binding is observed even in 10 % serum, thus enabling profiling of sialyl-glycan on cancer cells, as compared with the widely used lectin, Sambucus nigra. The synergistic binding mode between the best boronopeptide (P3) binder and sialic acid was analyzed via 1 H and 11 B NMR.

Identification, synthesis, and characterization of an unprecedented N-(2-carboxyethyl) adduct impurity in an injectable ganirelix formulation.

Ganirelix, a peptide-based drug used to treat female infertility, has been in high market demand, which attracted generic formulation. A hitherto unknown impurity of ganirelix was observed in our formulation process, which reached ~0.3% in 6 months and led to a detailed investigation of its structure. In-depth analysis of ESI-MS/MS data of this impurity coupled with an artificial intelligence prediction tool led to a highly unusual putative structure, that is, N-(2-carboxyethyl)-ganirelix (NCE-GA), which was authenticated by chemical synthesis from ganirelix and NMR analysis and via corroborated HPLC and MS/MS data with the formulation-derived impurity.

Unveiling the Prognostic Power of Coronary Physiological Progression.

Coronary atherosclerosis, a progressive disease, has long been the focus of clinical investigations aimed at understanding its natural evolution and response to medical therapies. While traditional imaging modalities, such as intravascular ultrasound (IVUS) and coronary computed tomography angiography (CTA), have shed light on plaque characteristics and vulnerability to rupture leading to clinical events, the clinical implications of coronary physiological techniques associated with increased risk of clinical events remain underexplored. The incremental prognostic value of 3V-quantitative flow ratio (QFR) advocates for its integration into routine clinical evaluations as a non-invasive tool for risk stratification in coronary artery disease patients.

Unmet Needs and Future Direction for Pulmonary Embolism Interventions.

Venous thromboembolism (VTE) usually develops in the deep veins of the extremities. Pulmonary embolism (PE) is a type of VTE that is most commonly (∼90%) caused by a thrombus that originates from the deep veins of the lower extremities. PE is the third most common cause of death after myocardial infarction and stroke. In this review, the authors investigate and discuss the risk stratification and definitions of the aforementioned categories of PE and further explore the management of acute PE along with the types of catheter-based treatment options and their efficacy.

Sulfonyl Diazaborine 'Click' Chemistry Enables Rapid and Efficient Bioorthogonal Labeling.

Finding an ideal bioorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho-carbonyl phenylboronic acid with α-nucleophiles is an attractive conjugation module. Nevertheless, these conjugation reactions demand to satisfy stringent criteria for bioorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho-carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. Remarkably, the reaction conversion is quantitative and rapid (k2 >103  M-1 s-1 ) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. DFT calculations support that SHz facilitates DAB formation via the most stable hydrazone intermediate and the lowest energy transition state compared to other biocompatible α-nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.

Cardiac Symptoms During the Russia-Ukraine War: A Google Trends Analysis.

Background The 2022 Ukraine-Russian War has led to significant anxiety, anguish, and trauma among the people in Ukraine. The objective of this study was to analyze the Google Trend results of common cardiac symptoms in Ukraine, Russia, and worldwide in 2022 and compare that to 2021 with the hypothesis that common cardiac symptoms in the war-affected regions would be higher compared to the rest of the world. We hypothesize that the search trends of cardiac symptoms would increase in Ukraine given the turmoil caused by the Russian invasion. Methods We queried Google Trends for common cardiac symptoms such as chest pain, dizziness, palpitations, syncope, etc. Google Trends provides results as relative search volume (RSV) displayed in a geographical format. The RSV ranges from 0 to 100, with 0 indicating that the search term is not popular, and 100 indicating the search term's popularity is at its peak. Google Trends of cardiac symptoms in Russia, Ukraine, and worldwide was taken two weeks before and after February 24, 2022, compared with the same period in 2021. To assess the difference in Google Trends between the study periods in 2022 and 2021, the paired t-test was used. Results Overall, Google Trends for cardiac symptoms was lower in Ukraine and Russia than worldwide, in both 2021 and 2022 during the study period. There was a significant reduction in search for chest pain (14 vs. 30.5; p<0.049), pedal edema (40.0 vs 66.6; p approaching 0), and syncope (37.8 vs. 58.4; p<0.002) in Ukraine during the study periods in 2022 compared to 2021. There was a decrease in the searches for dyspnea (44.6 vs. 55.4; p<0.029) in Russia and for dizziness (87.6 vs. 92.8; p<0.005) worldwide. There was an increase in the searches for edema (93.6 vs. 91; p <0.002) and for fatigue (88.6 vs 79.5; p approaching 0) worldwide in study periods in 2022 as compared to 2021. There was no other significant difference between cardiac symptom search trends during the periods evaluated in Ukraine, Russia, and worldwide. Conclusion There appears to be a significant reduction in searching for a few cardiovascular symptoms, namely, chest pain, pedal edema, and syncope in Ukraine, which may be due to a focus on other immediate problems related to war and the availability of the Internet.

Periprocedural Complications With Balloon Pulmonary Angioplasty: Analysis of Global Studies.

BACKGROUND: Balloon pulmonary angioplasty (BPA) was introduced as a treatment modality for patients with inoperable, medically refractory chronic thromboembolic pulmonary hypertension decades ago; however, reports of high rates of pulmonary vascular injury have led to considerable refinement in procedural technique. OBJECTIVES: The authors sought to better understand the evolution of BPA procedure-related complications over time. METHODS: The authors conducted a systematic review of original articles published by pulmonary hypertension centers globally and performed a pooled cohort analysis of procedure-related outcomes with BPA. RESULTS: This systematic review identified 26 published articles from 18 countries worldwide from 2013 to 2022. A total of 1,714 patients underwent 7,561 total BPA procedures with an average follow up of 7.3 months. From the first period (2013-2017) to the second period (2018-2022), the cumulative incidence of hemoptysis/vascular injury decreased from 14.1% (474/3,351) to 7.7% (233/3,029) (P < 0.01); lung injury/reperfusion edema decreased from 11.3% (377/3,351) to 1.4% (57/3,943) (P < 0.01); invasive mechanical ventilation decreased from 0.7% (23/3,195) to 0.1% (4/3,062) (P < 0.01); and mortality decreased from 2.0% (13/636) to 0.8% (8/1,071) (P < 0.01). CONCLUSIONS: Procedure-related complications with BPA, including hemoptysis/vascular injury, lung injury/reperfusion edema, mechanical ventilation, and death, were less common in the second period (2018-2022), compared with first period (2013-2017), likely from refinement in patient and lesion selection and procedural technique over time.

Cysteine-Selective Installation of Functionally Diverse Boronic Acid Probes on Peptides.

The current methods for direct late-stage and residue-selective installation of a versatile boronic acid (BA) repertoire on peptides are inadequate for a wide range of applications. Here, we show the suitability and efficiency of thiol-ene radical click chemistry to install functionally versatile BA derivatives on numerous bioactive, native peptides. Our work highlights that the methodology is operationally simple and adaptable for applications with BA-modified peptides, such as cyclization, conjugation, and functional group alteration.

Synthesis and characterization of two potential impurities (des-ethyl-Ganirelix) generated in the Ganirelix manufacturing process.

Controlling certain diseases using peptide drugs has remarkably increased in the past two decades. In this regard, a generic formulation is an upfront solution to fulfill market demands. Ganirelix, a leading peptide active pharmaceutical ingredient (API) primarily used as a gonadotropin-releasing hormone antagonist (GnRH), has established a potential market value worldwide. But its generic formulation mandates detailed impurity profiles from a synthetic source and contemplates the sameness of a reference-listed drug (RLD). Post-chemical synthesis and processing of Ganirelix, some commercial sources have revealed two new potential impurities among many known, which show the deletion of an ethyl group from the hArg(Et)2 residue at the sixth and eighth positions, named des-ethyl-Ganirelix. These impurities are unprecedented in traditional peptide chemistry, and such monoethylated-hArg building blocks are not easily accessible commercially to synthesize these two impurities. Here, we have outlined the synthesis, purification, and enantiomeric purity characterization of the amino acids and their incorporation in the Ganirelix peptide sequence to synthesize these potential peptide impurities. This methodology will enable the convenient synthesis of side-chain substituted Arg and hArg derivatives in peptide drug discovery platforms.

Rapid and Highly Productive Assembly of a Disulfide Bond in Solid-Phase Peptide Macrocyclization.

Here we report a highly efficient disulfide-driven peptide macrocyclization in 15 min on a solid support using persulfate as a crucial additive in iodine-mediated oxidative cyclization. The method eliminates the side products of classical iodine-mediated peptide cyclization. It is operationally simple and convenient for cyclizing small to lengthier peptides embodying popular cysteine building blocks in a single step.

Direct Oral Anticoagulants vs Vitamin K Antagonists in Patients With Antiphospholipid Syndromes: Meta-Analysis of Randomized Trials.

BACKGROUND: The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial. OBJECTIVES: The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs). METHODS: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used. RESULTS: Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I2 = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I2 = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I2 = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I2 = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups. CONCLUSIONS: Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.

Integrating a covalent probe with ubiquicidin fragment enables effective bacterial infection imaging.

Developing potent and novel bacterial imaging agents remains formidable due to the rapid development of bacterial resistance. Ubiquicidin and its derivatives are the most studied antimicrobial peptides that bind to anionic membranes of a broad range of bacterial pathogens. Studies reveal that UBI (29-41) labeled with 99mTc and 68Ga could distinguish sterile inflammation from infection. A significant challenge that remains for cationic peptides is their poor salt tolerance. The present study deliberates the increment of UBI (29-41) peptide interaction with the bacterial membrane by incorporating 2-acetylphenylboronic acid (2-APBA) as a covalent probe and developing infection imaging probes with improved retention at the target. Given that both 99mTc-UBI (29-41) and 99mTc-UBI (29-41)-2-APBA peptide complexes are stable in serum over 16 h, 99mTc-UBI (29-41)-2-APBA shows enhanced uptake in S. aureus cells as compared to 99mTc-UBI (29-41). SPECT imaging in a mouse model of infection exhibited a higher target to non-target ratio after 2 h in the case of 99mTc-UBI (29-41)-2-APBA. The present study reveals a synergistic mechanism of target binding through covalent conjugation and non-covalent interaction, which could be a potential strategy for improving bacterial infection imaging. As a proof of concept, 99mTc-UBI (29-41)-2-APBA elicits our hypothesis by in vivo imaging of bacterial infection.

Three versus 12-month dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials.

INTRODUCTION: The American Heart Association/American College of Cardiology guidelines on dual antiplatelet therapy (DAPT) recommend at least 12 months of a P2Y12 inhibitor and low dose aspirin in patients with an acute coronary syndrome (ACS) treated with a stent. Since that recommendation, several randomized controlled trials (RCTs) have studied an abbreviated duration of DAPT in ACS. Therefore, we sought to perform a meta-analysis of RCTs comparing 3- versus 12-month DAPT in patients presenting with ACS undergoing percutaneous coronary intervention (PCI). METHODS: PubMed, Embase, and Cochrane Central databases were searched until July 31, 2022, for RCTs comparing 3- versus 12-month DAPT in patients with ACS undergoing PCI. Outcomes assessed were major adverse cardiovascular events (MACE), cardiovascular mortality, all-cause mortality, myocardial infarction (MI), stent thrombosis (ST) and bleeding. A random-effects model was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI). RESULTS: We included 5 trials comprising 16,781 patients with an ACS that underwent PCI. There was no significant difference in MACE (RR: 0.92; 95% CI: 0.76-1.11), cardiovascular mortality (RR: 1.26; 95% CI: 0.38-4.17), or all-cause mortality (RR: 0.92; 95% CI: 0.48-1.77) between the 2 groups. In addition, there was no difference in rates of MI (RR: 0.98; 95% CI: 0.74-1.30), or ST (RR: 1.30; 95% CI: 0.55-3.05) between 3- and 12-month DAPT. However, compared with 12-month DAPT, 3-month DAPT significantly reduced risk of major bleeding (RR: 0.53; 95% CI: 0.43-0.64). CONCLUSIONS: In patients with ACS undergoing PCI, 3-month DAPT reduced risk of bleeding without evidence of harm.

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

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.