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Background: Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies.Objective: The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation.Design: The IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI.Conclusion: The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms. [ABSTRACT FROM AUTHOR]

BACKGROUND: Increased vasopressin levels may be present in patient with chronic heart failure (HF) and contribute to pathophysiology through effects on the vasopressin V2 receptor. The presence of background diuretic therapy may confound evaluations of vasopressin receptor antagonists (VRA). METHODS AND RESULTS: Eligible patients had HF (New York Heart Association Class II-III), systolic dysfunction (left ventricular ejection fraction <=0.40) and signs of congestion (eg, edema, rales). At screening, patients were removed from baseline diuretic therapy and placed on a low-sodium diet (2 g/day). After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), monotherapy with the vasopressin V2 receptor antagonist tolvaptan (TLV) 30 mg (n = 20), monotherapy with furosemide 80 mg (FURO, n = 22) or both TLV 30 mg and FURO 80 mg (n = 20) once daily for 7 days. Patients were on standard background therapy and not fluid-restricted throughout the study. A decrease in body weight of -1.37 ± 1.61, -0.54 ± 1.59, and -1.13 ± 1.49 kg was observed versus baseline for TLV, FURO, and TLV+FURO, respectively, at day 8. At the same point, the placebo group showed a body weight increase of +0.72 ± 2.42 kg versus baseline (P = .0006 for TLV versus placebo). Increases in urine volume from baseline were greater with TLV alone (2646 ± 1503 mL/24 hours) than with FURO (894 ± 853 mL/24 hours, P < .001), or PLC (423 ± 786 mL/24 hours, P < .001), and similar to TLV+FURO (2585 ± 2119 mL/24 hours). An increase in serum sodium within the normal range was also observed in TLV-treated patients (P < .02 versus placebo; P < .01 versus FURO). No changes in serum potassium, other laboratory values, or blood pressure were observed. TLV therapy was well tolerated. CONCLUSIONS: In patients with HF and signs of volume overload, TLV monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and [beta]-blockers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Suboptimal compliance in taking guideline-based pharmacotherapy in patients with chronic heart failure (HF) potentially increases the burden of hospitalizations and diminishes quality of life. By simplifying the medical regimen, once-daily dosing can potentially improve compliance. The Compliance And Quality of Life Study Comparing Once-Daily Controlled-Release Carvedilol CR and Twice-Daily Immediate-Release Carvedilol IR in Patients with Heart Failure (CASPER) Trial was designed to measure differential compliance, satisfaction, and quality of life in chronic HF patients taking carvedilol immediate release (IR) twice daily versus the bioequivalent carvedilol controlled-release (CR) once daily. METHODS AND RESULTS: CASPER was a prospective multicenter, 3-arm, parallel-group, randomized clinical trial for a 5-month period. The primary objective of the study was to evaluate and compare compliance with carvedilol IR twice daily (BID) and carvedilol phosphate CR once daily (QD) in patients with chronic HF who were taking carvedilol IR. Secondary objectives included comparisons of quality of life (Kansas City Cardiomyopathy Questionnaire), satisfaction with medication, and brain natriuretic peptide levels between subjects taking the two formulations. A total of 405 patients with chronic HF and left ventricular dysfunction were randomized to: (A) carvedilol IR twice daily, given double blind; (B) carvedilol CR taken in the morning and placebo in the afternoon, given double blind; or (C) carvedilol CR once daily, open label. Compliance was measured using the medication event monitoring system that captures time of bottle opening. The primary end point was a comparison of taking compliance (doses taken divided by total number of prescribed doses over the actual duration of the study) between the double-blind carvedilol IR BID versus the open-label carvedilol CR QD groups. Sample size estimates were based on assumptions of 75% compliance with BID dosing and 90% compliance with QD dosing. Mean compliance with carvedilol IR BID was 89.3% compared with 88.2% for carvedilol CR QD, and differential mean compliance was 1.1% (95% CI -4.4%, 6.6%; ie, not significant). There were no statistically significant differences in compliance between any of the 3 groups, nor differences in quality of life, treatment satisfaction, or physiologic measures among the 3 study arms. There were also no significant differences in adverse events or side effects among patients switching from carvedilol IR to carvedilol CR in arms B or C over the 5-month study duration compared with patients remaining on carvedilol IR. CONCLUSIONS: Compliance among chronic HF patients in the CASPER trial was high at baseline and unaffected by QD versus BID dosing. Over the 5-month follow-up period, there were no differences in adverse events among patients switching from carvedilol IR to CR. [ABSTRACT FROM AUTHOR]

Context: Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V2-receptor antagonist, shows promise in this condition.Objective: To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure.Design, Setting, and Patients: Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied.Intervention: Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission.Main Outcome Measures: Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge).Results: Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension.Conclusion: In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events.Trial Registration: clinicaltrials.gov Identifier: NCT00071331 [ABSTRACT FROM AUTHOR]

Context: Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker, shows promise for management of heart failure.Objective: To investigate the effects of tolvaptan initiated in patients hospitalized with heart failure.Design, Setting, and Participants: The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST), an event-driven, randomized, double-blind, placebo-controlled study. The outcome trial comprised 4133 patients within 2 short-term clinical status studies, who were hospitalized with heart failure, randomized at 359 North American, South American, and European sites between October 7, 2003, and February 3, 2006, and followed up during long-term treatment.Intervention: Within 48 hours of admission, patients were randomly assigned to receive oral tolvaptan, 30 mg once per day (n = 2072), or placebo (n = 2061) for a minimum of 60 days, in addition to standard therapy.Main Outcome Measures: Dual primary end points were all-cause mortality (superiority and noninferiority) and cardiovascular death or hospitalization for heart failure (superiority only). Secondary end points included changes in dyspnea, body weight, and edema.Results: During a median follow-up of 9.9 months, 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (hazard ratio, 0.98; 95% confidence interval [CI], 0.87-1.11; P = .68). The upper confidence limit for the mortality difference was within the prespecified noninferiority margin of 1.25 (P<.001). The composite of cardiovascular death or hospitalization for heart failure occurred in 871 tolvaptan group patients (42.0%) and 829 placebo group patients (40.2%; hazard ratio, 1.04; 95% CI, 0.95-1.14; P = .55). Secondary end points of cardiovascular mortality, cardiovascular death or hospitalization, and worsening heart failure were also not different. Tolvaptan significantly improved secondary end points of day 1 patient-assessed dyspnea, day 1 body weight, and day 7 edema. In patients with hyponatremia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups.Conclusion: Tolvaptan initiated for acute treatment of patients hospitalized with heart failure had no effect on long-term mortality or heart failure-related morbidity.Trial Registration: clinicaltrials.gov Identifier: NCT00071331 [ABSTRACT FROM AUTHOR]

Although early cardiac computed tomographic angiography (CCTA) might improve the management of emergency department (ED) patients with acute chest pain, it could also result in increased testing, costs, and radiation exposure. ROMICAT II was a randomized comparative effectiveness trial enrolling patients 40 to 74 years old without known coronary artery disease who presented to the ED with chest pain but without ischemic electrocardiographic (ECG) changes or elevated initial troponin and who required further risk stratification. Overall, 1000 patients at 9 sites within the United States were randomized to either CCTA as the first diagnostic test following serial biomarkers or to standard of care, which included no testing or functional testing such as exercise ECG, stress radionuclide imaging, or stress echocardiography. Test results were provided to ED physicians, yet patient management was not driven by a study protocol in either arm. Data were collected on diagnostic testing, cardiac events, and cost of medical care for the index hospitalization and during the following 28 days. The primary end point was length of hospital stay. Secondary end points were cumulative radiation exposure, resource utilization, and costs of competing strategies. Tertiary end points were institutional, physician, and patient characteristics associated with primary and secondary outcomes. Rate of missed acute coronary syndrome within 28 days was the safety end point. The ROMICAT II will provide rigorous data on whether CCTA is more efficient than standard of care in the management of patients with acute chest pain at intermediate risk for acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Background: The extent to which infarct artery impacts the extent of myocardial injury and outcomes in patients with ST-segment-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention is uncertain., Methods and Results: We performed a pooled analysis using individual patient data from 7 randomized STEMI trials in which myocardial injury within 30 days after primary percutaneous coronary intervention was assessed in 1774 patients by cardiac magnetic resonance (n=1318) or technetium-99m sestamibi single-photon emission computed tomography (n=456). Clinical follow-up was performed at a median duration of 351 days (interquartile range, 184-368 days). Infarct size and outcomes were assessed in anterior (infarct vessel=left anterior descending) versus nonanterior (non-left anterior descending) STEMI. Median infarct size (percentage left ventricular myocardial mass) was larger in patients with anterior compared with nonanterior STEMI (19.7% [interquartile range, 9.4%-31.7%] versus 12.6% [interquartile range, 5.1%-20.5%]; P <0.001). Patients with anterior compared with nonanterior STEMI were at higher risk for 1-year all-cause mortality (6.2% versus 3.6%; adjusted hazard ratio [HR], 1.66 [95% CI, 1.02-2.69]; P =0.04) and heart failure hospitalization (4.4% versus 2.6%; adjusted HR, 1.96 [95% CI, 1.15-3.36]; P =0.01). Infarct size was a predictor of subsequent all-cause mortality or heart failure hospitalization in anterior STEMI (adjusted HR per 1% increase, 1.05 [95% CI, 1.03-1.07]; P <0.001), but not in nonanterior STEMI (adjusted HR, 1.02 [95% CI, 0.99-1.05]; P =0.19). The P value for this interaction was 0.04., Conclusions: Anterior STEMI was associated with substantially greater myonecrosis after primary percutaneous coronary intervention compared with nonanterior STEMI, contributing in large part to the worse prognosis in patients with anterior infarction.

Background: Therapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF)., Objectives: This pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion., Methods: Participants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro-B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life., Results: Thirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was -2.02 kg at day 3 (95% CI: -3.9 to -0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%)., Conclusions: SC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure-A Pilot Study]; NCT04593823)., Competing Interests: Funding Support and Author Disclosures This study was funded by scPharmaceuticals, Inc. Dr M.A. Konstam has received personal fees from Alnylam, Boehringer-Ingelheim, Cardurian, LivaNova, scPharmaceuticals, Fire 1, Vicardia, and Alleviant. Dr Dhingra has received personal fees from scPharmaceuticals, Bristol Myers Squibb, and CareDx. Dr Walsh has received personal fees from scPharmaceuticals. Ms Ordway has received personal fees from scPharmaceuticals. Dr Pursley has received personal fees from scPharmaceuticals. Dr McLean has received personal fees from scPharmaceuticals. Mr Saha is a full-time employee of Cardiovascular Clinical Science Foundation. Dr Close is a full-time employee of EmpiriStat, Inc. Mr J.M. Konstam is a full-time employee of iQVIA. Dr Luepke is a full-time employee of scPharmaceuticals. Dr Mohr is a full-time employee of scPharmaceuticals. Dr Udelson has received personal fees from scPharmaceuticals, Merck, Alleviant, Reprieve CV, and Cardurion., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics., Objectives: This study sought to evaluate the safety and efficacy of ninerafaxstat in nHCM., Methods: Patients with hypertrophic cardiomyopathy and left ventricular outflow tract gradient <30 mm Hg, ejection fraction ≥50%, and peak oxygen consumption <80% predicted were randomized to ninerafaxstat 200 mg twice daily or placebo (1:1) for 12 weeks. The primary endpoint was safety and tolerability, with efficacy outcomes also assessed as secondary endpoints., Results: A total of 67 patients with nHCM were enrolled at 12 centers (57 ± 11.8 years of age; 55% women). Serious adverse events occurred in 11.8% (n = 4 of 34) in the ninerafaxstat group and 6.1% (n = 2 of 33) of patients in the placebo group. From baseline to 12 weeks, ninerafaxstat was associated with significantly better V E /Vco 2 (ventilatory efficiency) slope compared with placebo with a least-squares (LS) mean difference between the groups of -2.1 (95% CI: -3.6 to -0.6; P = 0.006), with no significant difference in peak VO 2 (P = 0.90). The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was directionally, though not significantly, improved with ninerafaxstat vs placebo (LS mean 3.2; 95% CI: -2.9 to 9.2; P = 0.30); however, it was statistically significant when analyzed post hoc in the 35 patients with baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary Score ≤80 (LS mean 9.4; 95% CI: 0.3-18.5; P = 0.04)., Conclusions: In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a phase 3 study., Competing Interests: Funding Support and Author Disclosures Imbria Pharmaceuticals contributed significant funding to this study. Dr Neubauer acknowledges support from the Oxford NIHR Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. Dr Valkovic is supported by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (#221805/Z/20/Z), and also acknowledges the support from the Oxford BHF Centre of Research Excellence and from the Slovak Grant Agencies VEGA (#2/0004/23) and APVV (#21-0299). Dr Samat was supported by a doctoral scholarship funded by the Ministry of Higher Education Malaysia and National University of Malaysia. Dr Maron has served on the steering committee for SEQUOIA-HCM; and has received consultant/advisor fees from Cytokinetics, Imbria, and Edgewise. Dr Mahmod has served as an investigator for SEQUOIA-HCM, FOREST-HCM (Cytokinetics), and EMPA-VISION (Boehringer Ingelheim). Dr Massera has received consulting fees from Sanofi, Tenaya Therapeutics, and Chiesi Pharmaceuticals. Dr Cresci has served on the data monitoring committee for the SEQUOIA-HCM, MAPLE-HCM, and ACACIA-HCM trials (Cytokinetics). Dr Martinez has served on the steering committee for ACACIA-HCM; and has received consultant/advisor fees from Cytokinetics and BMS. Dr Masri has received research grants from Pfizer, Ionis, Attralus, and Cytokinetics; and has received consultancy/advisory fees from Cytokinetics, BMS, Eidos/BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Prothena, BioMarin, AstraZeneca, and Tenaya. Dr Adler is currently the chief medical officer and head of research at Lexeo Therapeutics; has equity holdings in Lexeo Therapeutics, Rocket Pharmaceuticals, and Papillion Therapeutics; and has served on advisory boards for Cytokinetics and Kiniksa Pharmaeuticals. Dr Wever-Pinzon has received speaker fees from Bristol Myers Squibb. Dr Lewis has received research support and/or served as a consultant for the National Institutes of Health, American Reagent, Amgen, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Cardiage, Cytokinetics, Edwards, Imbria, Lilly, Merck, Novartis, NXT, Pfizer, and Rivus. Drs Chamberlin and Patel are salaried employees of Imbria Pharmaceuticals. Dr Yavari has served as a consultant for Imbria Pharmaceuticals; and is an employee of Weatherden Ltd. Dr Dehbi has received consulting fees from Imbria Pharmaceuticals. Dr Sarwar has received consulting fees from Imbria Pharmaceuticals and Ultromics. Dr Udelson has served as a member of the data and safety monitoring committee for the trial and has received consulting fees from Imbria Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The STEMI-DTU pilot study tested the early safety and practical feasibility of left ventricular (LV) unloading with a trans-valvular pump before reperfusion. In the intent-to-treat cohort, no difference was observed for microvascular obstruction (MVO) or infarct size (IS) normalized to either the area at risk (AAR) at 3-5 days or total LV mass (TLVM) at 3-5 days We now report a per protocol analysis of the STEMI-DTU pilot study., Methods: In STEMI-DTU STUDY 50 adult patients (25 in each arm) with anterior STEMI [sum of precordial ST-segment elevation (ΣSTE) ≥4 mm] requiring primary percutaneous coronary intervention (PCI) were enrolled. Only patients who met all inclusion and exclusion criteria were included in this analysis. Cardiac magnetic resonance (CMR) imaging 3-5 days after PCI quantified IS/AAR and IS/TLVM and MVO. Group differences were assessed using Student's t-tests and linear regression (SAS Version-9.4)., Results: Of the 50 patients enrolled, 2 died before CMR imaging. Of the remaining 48 patients those without CMR at 3-5 days (n = 8), without PCI of a culprit left anterior descending artery lesion (n = 2), with OHCA (n = 1) and with ΣSTE < 4 mm (n = 5) were removed from this analysis leaving 32/50 (64 %) patients meeting all inclusion and exclusion criteria (U-IR, n = 15; U-DR, n = 17) as per protocol. Despite longer symptom-to-balloon times in the U-DR arm (228 ± 80 vs 174 ± 59 min, p < 0.01), IS/AAR was significantly lower with 30 min of delay to reperfusion in the presence of active LV unloading (47 ± 16 % vs 60 ± 15 %, p = 0.02) and remained lower irrespective of the magnitude of precordial ΣSTE. MVO was not significantly different between groups (1.5 ± 2.8 % vs 3.5 ± 4.8 %, p = 0.15). Among patients who received LV unloading within 180 min of symptom onset, IS/AAR was significantly lower in the U-DR group., Conclusion: In this per-protocol analysis of the STEMI-DTU pilot study we observed that LV unloading for 30 min before reperfusion significantly reduced IS/AAR compared to LV unloading and immediate reperfusion, whereas in the ITT cohort no difference was observed between groups. This observation supports the design of the STEMI-DTU pivotal trial and suggests that strict adherence to the study protocol can significantly influence the outcome., Competing Interests: Declaration of competing interest NKK, JEU, WWO, GWS receive consulting/speaking honoraria from Abiomed. MP, AK, RHK, JWM, NA and HF have no relevant disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Quality-of-care and safety of patients with suspected acute coronary syndrome (ACS) would benefit if management was independent of which high-sensitivity cardiac troponin (hs-cTn) assay was used for risk stratification. We aimed to determine the concordance of hs-cTn assays to risk-stratify patients with suspected ACS according to the European Society of Cardiology (ESC) 2020 Guidelines., Methods and Results: Blood samples were obtained at arrival and at 2 h from patients with suspected ACS using four hs-cTn assays. The patients were classified into rule-out/observe/rule-in strata based on the ESC 2020 Guidelines. Concordance was determined among the assays for rule-out/observe/rule-in strata. The prevalences of significant underlying disease (≥50% stenosis on coronary computed tomography or inducible myocardial ischaemia on stress testing) and adjudicated ACS, plus quality-of-care outcomes, were compared. Among 238 patients (52.7 ± 8.0 years; 40.3% female), the overall concordance across assays to classify patients into rule-out/observe/rule-in strata was 74.0% (176/238). Platforms significantly differed for rule-out (89.9 vs. 76.5 vs. 78.6 vs. 86.6%, P < 0.001) and observe strata (6.7 vs. 20.6 vs. 17.7 vs. 9.2%, P < 0.001), but not for rule-in strata (3.4 vs. 2.9 vs. 3.8 vs. 4.2%, P = 0.62). Among patients in ruled-out strata, 19.1-21.6% had significant underlying disease and 3.3-4.2% had ACS. The predicted disposition of patients and cost-of-care differed across the assays (all P < 0.001). When compared with observed strata, conventional troponin-based management and predicted quality-of-care outcomes significantly improved with hs-cTn-based strategies (direct discharge: 21.0 vs. 80.3-90.8%; cost-of-care: $3889 ± 4833 vs. $2578 ± 2896-2894 ± 4371, all P < 0.001)., Conclusion: Among individuals with suspected ACS, patient management may differ depending on which hs-cTn assay is utilized. More data are needed regarding the implications of inter-assay differences., Trail Registration: NCT01084239., Competing Interests: Conflict of interest: J.T.N. has received research funds from Roche Diagnostics, Ortho Diagnostics, and Alere/Biosite to the Massachusetts General Hospital unrelated to this research. W.F.P. has received grant support from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, ImmunArray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, Roche, Salix, and Siemens; consulting income from Abbott, Astra-Zeneca, Bayer, Beckman, Boehringer Ingelheim, Ischemia Care, Dx, ImmunArray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, Salix, and Siemens; expert testimony from Johnson and Johnson; and reports stock/ownership interest for AseptiScope Inc., Brainbox Inc., Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC unrelated to this research. M.T.L. reports funding to his institution from Astra-Zeneca/MedImmune and Kowa and consulting fees from PQBypass unrelated to this research. B.M. reports personal fees from Biotronik, Abbott, Astra-Zeneca, Boehringer Ingelheim, and Novartis and institutional grants from Medtronic and Boston Scientific unrelated to this research. J.L.J. is a Trustee of the American College of Cardiology; is a Board member of Imbria Pharmaceuticals; has received grant support from Abbott, Applied Therapeutics, Innolife, HeartFlow, Janssen, Novartis Pharmaceuticals, and Roche Diagnostics; has received consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics; and participates in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Boehringer Ingelheim, CVRx, Intercept, Eidos, Janssen, and Takeda unrelated to this research. W.K. reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Genentech, Esperion, Amarin, Daiichi-Sanky, OMEICOS, Novo Nordisk, and Sanofi and grants and non-financial support from Beckmann, Singulex, Abbott, and Roche Diagnostics unrelated to this research. M.F. was supported by the grant from the American Heart Association (Fellow to Faculty Award #13FTF16450001) and has received consulting income from Biograph, Inc., Siemens Healthineers, and Elucid unrelated to this research. U.H. reported receiving research support from Duke University (Abbott), HeartFlow, Kowa Company Limited, and MedImmune/Astrazeneca and receiving consulting fees from Duke University (NIH), Recor Medical, Clinical Cardiovascular Sciences, and MedTrace unrelated to this research. The remaining authors have reported nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Flurpiridaz F-18 (flurpiridaz) is a novel positron emission tomography (PET) myocardial perfusion imaging tracer., Objectives: The purpose of this study was to further assess the diagnostic efficacy and safety of flurpiridaz for the detection and evaluation of coronary artery disease (CAD) defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA)., Methods: In this second phase 3 prospective multicenter clinical study, 730 patients with suspected CAD from 48 clinical sites in the United States, Canada, and Europe were enrolled. Patients underwent 1-day rest/stress flurpiridaz PET and 1- or 2-day rest-stress Tc-99m-labeled single photon emission computed tomography (SPECT) before ICA. PET and SPECT images were read by 3 experts blinded to clinical and ICA data., Results: A total of 578 patients (age 63.7 ± 9.5 years) were evaluable; 32.5% were women, 52.3% had body mass index ≥30 kg/m 2 , and 33.6% had diabetes. Flurpiridaz PET met the efficacy endpoints of the study; its sensitivity and specificity were significantly higher than the prespecified threshold value by 2 of the 3 readers. The sensitivity of flurpiridaz PET was higher than SPECT (80.3% vs 68.7%; P = 0.0003) and its specificity was noninferior to SPECT (63.8% vs 61.7%; P = 0.0004). PET area under the receiver-operating characteristic curves were higher than SPECT in the overall population (0.80 vs 0.68; P < 0.001), women, and obese patients (P < 0.001 for both). Flurpiridaz PET was superior to SPECT (P < 0.001) for perfusion defect size/severity evaluation, image quality, diagnostic certainty, and radiation exposure. Flurpiridaz PET was safe and well tolerated., Conclusions: This second flurpiridaz PET myocardial perfusion imaging trial shows that flurpiridaz has utility as a new tracer for CAD detection, specifically in women and obese patients. (An International Study to Evaluate Diagnostic Efficacy of Flurpiridaz [18F] Injection PET MPI in the Detection of Coronary Artery Disease [CAD]; NCT03354273)., Competing Interests: Funding Support and Author Disclosures This study was funded by GE Healthcare Ltd and its Affiliates, Chalfont St Giles, United Kingdom. Drs Bax, Dorbala, Garcia, Heller, Tamaki, and Udelson have served as a consultant to GE Healthcare Ltd and its Affiliates. Drs Maddahi, Agostini, Bateman, Beanlands, Berman, and Knuuti have served as a consultant to and received a research grant from GE Healthcare Ltd and its Affiliates. Dr Beanlands has served as a consultant for and received research grants from Lantheus Medical Imaging and Jubilant DraxImage. Drs Feldman, Martinez-Clark, Pelletier-Galarneau, and Shepple have received a research grant from GE Healthcare Ltd and its Affiliates. Dr Tranquart is an employee and Global Head of Development of GE Healthcare Ltd and its Affiliates., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization., Objective: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT)., Design, Setting, and Participants: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT., Interventions: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care., Main Outcomes and Measures: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use., Results: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001)., Conclusions and Relevance: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety., Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Importance: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy., Objective: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred., Design, Setting, and Participants: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included., Intervention: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk., Main Outcome: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months., Results: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups., Conclusion and Relevance: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing., Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.