Milrinone vs Dobutamine for the Management of Cardiogenic Shock: Implications of Renal Function and Injury.

Background: Cardiogenic shock is associated with poor clinical outcomes. There is a paucity of prospective data examining the efficacy and safety of inotropic therapy in patients with cardiogenic shock and renal dysfunction. Objectives: This study sought to examine the treatment effect of milrinone compared to dobutamine in relation to renal function. Methods: In this post hoc analysis of the DOREMI (Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock) trial, we examined clinical outcomes with milrinone compared to dobutamine after stratification based on baseline estimated glomerular filtration rate (eGFR) 60 ml/min/1.73 m2 and acute kidney injury (AKI). The primary outcome was the composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Results: Baseline eGFR <60 ml/min/1.73 m2 and AKI were observed in 78 (45%) and 124 (65%) of patients, respectively. The primary outcome and death from any cause occurred in 99 (52%) and 76 (40%) patients, respectively. eGFR <60 ml/min/1.73 m2 did not appear to modulate the treatment effect of milrinone compared to dobutamine. In contrast, there was a significant interaction between the treatment effect of milrinone compared to dobutamine and AKI with respect to the primary outcome (P interaction = 0.02) and death (P interaction = 0.04). The interaction was characterized by lower risk of primary outcome and death with milrinone compared to dobutamine in patients without, but not with, AKI. Conclusions: In patients requiring inotropic support for cardiogenic shock, baseline renal dysfunction and AKI are common. A modulating effect of AKI on the relative efficacy of milrinone compared to dobutamine was observed, characterized by attenuation of a potential clinical benefit with milrinone compared to dobutamine in patients who develop AKI.

Determinants of long-term dual antiplatelet therapy use in post myocardial infarction patients: Insights from the TIGRIS registry.

BACKGROUND: Patterns of dual antiplatelet therapy (DAPT) use beyond 1 year post-myocardial infarction (MI) have not been well studied. METHODS: TIGRIS (NCT01866904) was a prospective, multi-center (369 centers in 24 countries), observational study of patients 1 to 3 years post-MI. We sought to identify the prevalence and determinants of DAPT use ≥1 year post-MI in patients enrolled in TIGRIS. We used multivariable logistic regression to identify determinants of DAPT use at 396 days post-MI (365 days plus a 31day overrun period to account for intended DAPT discontinuation at 1 year). Patients treated with an oral anticoagulant were excluded. RESULTS: Of 7708 patients (median age 67 years, women 25%, ST-elevation MI 50%), 39% and 16% were on DAPT at 396 days and 5 years post-MI, respectively. DAPT use at 396 days post-MI was more prevalent in patients <65 years of age, treated with percutaneous coronary intervention (versus coronary artery bypass grafting or medical therapy), and with multivessel disease or a history of angina. Additional clinical determinants of ischemic and/or bleeding events following MI (diabetes, second prior MI, hypertension, peripheral artery disease, heart failure, smoking, and renal insufficiency) were not independently associated with DAPT use at 396 days. There were geographic variations in the use of DAPT at 396 days (p<0.001), with the lowest use in Europe and the highest in Asia and Australia. CONCLUSION: In a contemporary patient cohort, DAPT use beyond 1 year post MI was prevalent and associated with patient and index event characteristics. There were marked geographical variations in DAPT use beyond 1 year post MI.

Outcomes of retrograde chronic total occlusion percutaneous coronary intervention: A report from the OPEN-CTO registry.

OBJECTIVES: We sought to assess in-hospital and long-term outcomes of retrograde compared with antegrade-only percutaneous coronary intervention for chronic total occlusion (CTO PCI). BACKGROUND: Procedural and clinical outcomes following retrograde compared with antegrade-only CTO PCI remain unknown. METHODS: Using the core-lab adjudicated OPEN-CTO registry, we compared the outcomes of retrograde to antegrade-only CTO PCI. Primary endpoints included were in-hospital major adverse cardiac and cerebrovascular events (MACCE) (all-cause death, stroke, myocardial infarction [MI], emergency cardiac surgery, or clinically significant perforation) and MACCE at 1-year (all-cause death, MI, stroke, target lesion revascularization, or target vessel reocclusion). RESULTS: Among 885 single CTO procedures from the OPEN-CTO registry, 454 were retrograde and 431 were antegrade-only. Lesion complexity was higher (J-CTO score: 2.7 vs. 1.9; p < .001) and technical success lower (82.4 vs. 94.2%; p < .001) in retrograde compared with antegrade-only procedures. All-cause death was higher in the retrograde group in-hospital (2 vs. 0%; p = .003), but not at 1-year (4.9 vs. 3.3%; p = .29). Compared with antegrade-only procedures, in-hospital MACCE rates (composite of all-cause death, stroke, MI, emergency cardiac surgery, and clinically significant perforation) were higher in the retrograde group (10.8 vs. 3.3%; p < .001) and at 1-year (19.5 vs. 13.9%; p = .03). In sensitivity analyses landmarked at discharge, there was no difference in MACCE rates at 1 year following retrograde versus antegrade-only CTO PCI. Improvements in Seattle Angina Questionnaire Quality of Life scores at 1-year were similar between the retrograde and antegrade-only groups (29.9 vs 30.4; p = .58). CONCLUSIONS: In the OPEN-CTO registry, retrograde CTO procedures were associated with higher rates of in-hospital MACCE compared with antegrade-only; however, post-discharge outcomes, including quality of life improvements, were similar between technical modalities.

Performance of Plasma Adenosine as a Biomarker for Predicting Cardiovascular Risk.

Adenosine boasts promising preclinical and clinical data supporting a vital role in modulating vascular homeostasis. Its widespread use as a diagnostic and therapeutic agent have been limited by its short half-life and complex biology, though adenosine-modulators have shown promise in improving vascular healing. Moreover, circulating adenosine has shown promise in predicting cardiovascular (CV) events. We sought to delineate whether circulating plasma adenosine levels predict CV events in patients undergoing invasive assessment for coronary artery disease. Patients undergoing invasive angiography had clinical data prospectively recorded in the Cardiovascular and Percutaneous ClInical TriALs (CAPITAL) revascularization registry and blood samples collected in the CAPITAL Biobank from which adenosine levels were quantified. Tertile-based analysis was used to assess prediction of major adverse cardiovascular events (MACE; composite of death, myocardial infarction, unplanned revascularization, and cerebrovascular accident). Secondary analyses included MACE subgroups, clinical subgroups and adenosine levels. There were 1,815 patients undergoing angiography who had blood collected with adenosine quantified in 1,323. Of those quantified, 51.0% were revascularized and 7.3% experienced MACE in 12 months of follow-up. Tertile-based analysis failed to demonstrate any stratification of MACE rates (log rank, P = 0.83), when comparing low-to-middle (hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.68-1.78, P = 0.70) or low-to-high adenosine tertiles (HR 0.95, 95% CI 0.56-1.57, P = 0.84). In adjusted analysis, adenosine similarly failed to predict MACE. Finally, adenosine did not predict outcomes in patients with acute coronary syndrome nor in those revascularized or treated medically. Plasma adenosine levels do not predict subsequent CV outcomes or aid in patient risk stratification.

Evaluation of Plasma Adenosine as a Marker of Cardiovascular Risk: Analytical and Biological Considerations.

Background Adenosine is a ubiquitous regulatory molecule known to modulate signaling in many cells and processes vital to vascular homeostasis. While studies of adenosine receptors have dominated research in the field, quantification of adenosine systemically and locally remains limited owing largely to technical restrictions. Given the potential clinical implications of adenosine biology, there is a need for adequately powered studies examining the role of plasma adenosine in vascular health. We sought to describe the analytical and biological factors that affect quantification of adenosine in humans in a large, real-world cohort of patients undergoing evaluation for coronary artery disease. Methods and Results Between November 2016 and April 2018, we assessed 1141 patients undergoing angiography for evaluation of coronary artery disease. High-performance liquid chromatography was used for quantification of plasma adenosine concentration, yielding an analytical coefficient of variance (CVa) of 3.2%, intra-subject variance (CVi) 35.8% and inter-subject variance (CVg) 56.7%. Traditional cardiovascular risk factors, medications, and clinical presentation had no significant impact on adenosine levels. Conversely, increasing age (P=0.027) and the presence of obstructive coronary artery disease (P=0.026) were associated with lower adenosine levels. Adjusted multivariable analysis supported only age being inversely associated with adenosine levels (P=0.039). Conclusions Plasma adenosine is not significantly impacted by traditional cardiovascular risk factors; however, advancing age and presence of obstructive coronary artery disease may be associated with lower adenosine levels. The degree of intra- and inter-subject variance of adenosine has important implications for biomarker use as a prognosticator of cardiovascular outcomes and as an end point in clinical studies.

Ischemic and bleeding outcomes after coronary artery bypass grafting among patients initially treated with a P2Y12 receptor antagonist for acute coronary syndromes: Insights on timing of discontinuation of ticagrelor and clopidogrel prior to surgery.

BACKGROUND: Clinical outcomes in acute coronary syndrome patients treated with P2Y12 inhibitors who require urgent coronary artery bypass grafting (CABG) have not been well studied. METHODS: We examined clinical outcomes in acute coronary syndrome patients in relation to the timing of CABG following P2Y12 inhibitor discontinuation (<72 h, 72 h to five days, >5 days). The primary ischemic outcome was a composite of death, reinfarction, need for revascularization, or stroke. The primary safety outcome was bleeding of at least moderate severity as defined by a Universal Definition of Perioperative Bleeding class ≥2. RESULTS: Among 508 patients (95 ticagrelor, 413 clopidogrel), the timing of CABG following P2Y12 inhibitor discontinuation was <72 h in 32.1%, 72 h to five days in 23.2% and >5 days in 44.7%. Compared with CABG within 72 h, CABG 72 h to five days (adjusted odds ratio (OR) 0.35; 95% confidence interval (CI) 0.14-0.85; p=0.02) but not >5 days (adjusted OR 0.62; 95% CI 0.33-1.16; p=0.14) after P2Y12 inhibitor discontinuation was associated with lower odds of the primary ischemic outcome. Compared with CABG within 72 h, CABG 72 h to five days (adjusted OR 0.38; 95% CI 0.22-0.66; p=0.001) and >5 days (adjusted OR 0.33; 95% CI 0.20-0.53; p<0.001) after P2Y12 inhibitor discontinuation were associated with lower rates of Universal Definition of Perioperative Bleeding class ≥2 bleeding. CONCLUSIONS: CABG within 72 h after P2Y12 inhibitor discontinuation is associated with excess ischemia and bleeding. The rates of ischemic and bleeding events were comparable in patients undergoing CABG 72 h to five days compared with >5 days after P2Y12 inhibitor discontinuation.

Adenosine as a Marker and Mediator of Cardiovascular Homeostasis: A Translational Perspective.

Adenosine, a purine nucleoside, is produced broadly and implicated in the homeostasis of many cells and tissues. It signals predominantly via 4 purinergic adenosine receptors (ADORs) - ADORA1, ADORA2A, ADORA2B and ADOosine signaling, both through design as specific ADOR agonists and antagonists and as offtarget effects of existing anti-platelet medications. Despite this, adenosine has yet to be firmly established as either a therapeutic or a prognostic tool in clinical medicine to date. Herein, we provide a bench-to-bedside review of adenosine biology, highlighting the key considerations for further translational development of this proRA3 in addition to non-ADOR mediated effects. Through these signaling mechanisms, adenosine exerts effects on numerous cell types crucial to maintaining vascular homeostasis, especially following vascular injury. Both in vitro and in vivo models have provided considerable insights into adenosine signaling and identified targets for therapeutic intervention. Numerous pharmacologic agents have been developed that modulate adenmising molecule.

Duration of dual antiplatelet therapy and associated outcomes following percutaneous coronary intervention for acute myocardial infarction: contemporary practice insights from the Canadian Observational Antiplatelet Study.

Aims: There is a paucity of real-world, contemporary data of practice patterns and clinical outcomes following dual-antiplatelet therapy (DAPT) in acute myocardial infarction (AMI) patients treated with percutaneous coronary intervention (PCI). Methods and results: The Canadian Observational Antiplatelet Study was a prospective, multicentre, cohort study examining adenosine diphosphate receptor antagonist use following PCI for AMI. We compared practice patterns, patient characteristics, and clinical outcomes in relation to DAPT duration (<6 weeks, 6 weeks to <6 months, 6 to <12, and ≥12 months). The primary outcome was the composite of non-fatal AMI, unplanned coronary revascularization, stent thrombosis, new or worsening heart failure, cardiogenic shock, or stroke. We identified 2034 patients with AMI treated with PCI. DAPT duration was <6 weeks in 5.2% of patients; 6 weeks to <6 months in 7.0%; 6 to <12 months in 12.6%; and ≥12 months in 75.3%. Patients who discontinued DAPT early had higher GRACE risk scores. Overall, mortality rate at 15 months was 2.5%. Compared with a duration of DAPT of ≥12 months, discontinuation of DAPT <6 weeks (P < 0.0001) and 6 weeks to <6 months (P = 0.02), but not 6 months to <12 months (P = 0.06), were independently associated with a higher incidence of the primary outcome among survivors. Conclusion: One-in-four patients with AMI treated with PCI discontinued DAPT prior to the guideline-recommended 12-month duration. Patients in whom DAPT was discontinued early were at higher baseline risk and had higher rates of non-fatal ischaemic events during follow up.

Progenitor Cells for Arterial Repair: Incremental Advancements towards Therapeutic Reality.

Coronary revascularization remains the standard treatment for obstructive coronary artery disease and can be accomplished by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. Considerable advances have rendered PCI the most common form of revascularization and improved clinical outcomes. However, numerous challenges to modern PCI remain, namely, in-stent restenosis and stent thrombosis, underscoring the importance of understanding the vessel wall response to injury to identify targets for intervention. Among recent promising discoveries, endothelial progenitor cells (EPCs) have garnered considerable interest given an increasing appreciation of their role in vascular homeostasis and their ability to promote vascular repair after stent placement. Circulating EPC numbers have been inversely correlated with cardiovascular risk, while administration of EPCs in humans has demonstrated improved clinical outcomes. Despite these encouraging results, however, advancing EPCs as a therapeutic modality has been hampered by a fundamental roadblock: what constitutes an EPC? We review current definitions and sources of EPCs as well as the proposed mechanisms of EPC-mediated vascular repair. Additionally, we discuss the current state of EPCs as therapeutic agents, focusing on endogenous augmentation and transplantation.