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Background: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention., Methods: This was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted between November 2017 to November 2021 in 6 cardiac centers in Singapore. Patients were randomized to receive either cangrelor or placebo initiated before the primary percutaneous coronary intervention procedure on top of oral ticagrelor. The key exclusion criteria included presenting <6 hours of symptom onset; previous MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance. The primary efficacy end point was acute MI size by cardiovascular magnetic resonance within the first week expressed as percentage of the left ventricle mass (%LVmass). Microvascular obstruction was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety end point was Bleeding Academic Research Consortium-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test (reported as median [first quartile-third quartile]), and categorical variables were compared by Fisher exact test. A 2-sided P <0.05 was considered statistically significant., Results: Of 209 recruited patients, 164 patients (78%) completed the acute cardiovascular magnetic resonance scan. There were no significant differences in acute MI size (placebo, 14.9% [7.3-22.6] %LVmass versus cangrelor, 16.3 [9.9-24.4] %LVmass; P =0.40) or the incidence (placebo, 48% versus cangrelor, 47%; P =0.99) and extent of microvascular obstruction (placebo, 1.63 [0.60-4.65] %LVmass versus cangrelor, 1.18 [0.53-3.37] %LVmass; P =0.46) between placebo and cangrelor despite a 2-fold decrease in platelet reactivity with cangrelor. There were no Bleeding Academic Research Consortium-defined major bleeding events in either group in the first 48 hours., Conclusions: Cangrelor administered at the time of primary percutaneous coronary intervention did not reduce acute MI size or prevent microvascular obstruction in patients with ST-segment-elevation MI given oral ticagrelor despite a significant reduction of platelet reactivity during the percutaneous coronary intervention procedure., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03102723., Competing Interests: L.T. is on the Astra Zeneca international advisory board of management of adverse events with the new antibody drug conjugate T-DXd in Asian patients with metastatic breast cancer, Roche Singapore immunotherapy in early stage NSCLC patient journey advisory board. L.T. has received a Philips speaker honorarium in kind and a Siemens Healthineers speaker honorarium. Y.K.K. has received research funding from Amgen, Astra Zeneca, Abbott Vascular, Bayer, Boston Scientific, Shockwave Medical, and Novartis (via institution); consulting fees from Abbott Vascular, Medtronic, Novartis, and Peijia Medical; and speaker fees from Shockwave Medical, Abbott Vascular, Boston Scientific, Medtronic, Alvimedica, Biotronik, Orbus Neich, Amgen, Novartis, Astra Zeneca, Microport, Terumo, and Omnicare. Y.K.K. is also cofounder and owns equity in Trisail, for which OrbusNeich is an investor. D.J.H. has received consultant fees from Faraday Pharmaceuticals Inc and Boehringer Ingelheim International GmbH, honoraria from Servier, and research funding from Astra Zeneca and Merck Sharp & Dohme Corp. C.Y.C. has received speaker fees from Novartis and consultancy fees from Boston Scientific and Philips. The other authors report no conflicts.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Background: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery., Methods: We used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF., Results: In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4, and follistatin-related protein-3, as well., Conclusions: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.

Background: There is a paucity of data from large cohort studies examining the prognostic significance of obstructive sleep apnea (OSA) in patients with coronary artery disease. We hypothesized that OSA predicts subsequent major adverse cardiac and cerebrovascular events (MACCEs) in patients undergoing percutaneous coronary intervention., Methods and Results: The Sleep and Stent Study was a prospective, multicenter registry of patients successfully treated with percutaneous coronary intervention in 5 countries. Between December 2011 and April 2014, 1748 eligible patients were prospectively enrolled. The 1311 patients who completed a sleep study within 7 days of percutaneous coronary intervention formed the cohort for this analysis. Drug-eluting stents were used in 80.1% and bioresorbable vascular scaffolds in 6.3% of the patients, and OSA, defined as an apnea-hypopnea index of ≥15 events per hour, was found in 45.3%. MACCEs, a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned revascularization, occurred in 141 patients during the median follow-up of 1.9 years (interquartile range, 0.8 years). The crude incidence of an MACCEs was higher in the OSA than the non-OSA group (3-year estimate, 18.9% versus 14.0%; p=0.001). Multivariate Cox regression analysis indicated that OSA was a predictor of MACCEs, with an adjusted hazard ratio of 1.57 (95% confidence interval, 1.10-2.24; P=0.013), independently of age, sex, ethnicity, body mass index, diabetes mellitus, and hypertension., Conclusions: OSA is independently associated with subsequent MACCEs in patients undergoing percutaneous coronary intervention. Evaluation of therapeutic approaches to mitigate OSA-associated risk is warranted., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01306526., (© 2016 American Heart Association, Inc.)

Background: The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007., Methods and Results: This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal., Conclusions: This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.