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Background: Accumulating evidence from clinical trials suggests that a lower (restrictive) hemoglobin threshold (<8 g/dL) for red blood cell (RBC) transfusion, compared with a higher (liberal) threshold (≥10 g/dL) is safe. However, in anemic patients with acute myocardial infarction (MI), maintaining a higher hemoglobin level may increase oxygen delivery to vulnerable myocardium resulting in improved clinical outcomes. Conversely, RBC transfusion may result in increased blood viscosity, vascular inflammation, and reduction in available nitric oxide resulting in worse clinical outcomes. We hypothesize that a liberal transfusion strategy would improve clinical outcomes as compared to a more restrictive strategy., Methods: We will enroll 3500 patients with acute MI (type 1, 2, 4b or 4c) as defined by the Third Universal Definition of MI and a hemoglobin <10 g/dL at 144 centers in the United States, Canada, France, Brazil, New Zealand, and Australia. We randomly assign trial participants to a liberal or restrictive transfusion strategy. Participants assigned to the liberal strategy receive transfusion of RBCs sufficient to raise their hemoglobin to at least 10 g/dL. Participants assigned to the restrictive strategy are permitted to receive transfusion of RBCs if the hemoglobin falls below 8 g/dL or for persistent angina despite medical therapy. We will contact each participant at 30 days to assess clinical outcomes and at 180 days to ascertain vital status. The primary end point is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary end points include all-cause mortality at 30 days, recurrent adjudicated MI, and the composite outcome of all-cause mortality, nonfatal recurrent MI, ischemia driven unscheduled coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or readmission to the hospital for ischemic cardiac diagnosis within 30 days. The trial will assess multiple tertiary end points., Conclusions: The MINT trial will inform RBC transfusion practice in patients with acute MI., Competing Interests: Disclosures JLC: DSMB member for Cerus Corporation project. MMB: DSMB member for Cerus Corporation project. JDA: Research funding MicroPort, Boston Scientific. Advisory Boards Philips, Medtronic. Consulting Abbott, Shockwave, Penumbra, Recor. SGG: Research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from: Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, TIMI Study Group (Brigham Health). AMG: None. MHB: None. Philippe Gabriel Steg: has received research grants from Bayer, Merck, Sanofi, Servier; has been a speaker or consultant for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers-Squibb, Janssen, Lexicon, Merck, Novartis, Novo-Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, Servier. He is a Senior Associate Editor for Circulation. APD: Consultant Velakor Biotherapeutics Inc. RDL: Grants from Bristol-Myers Squibb, GlaxoSmithKline plc., Medtronic, Pfizer, Bayer, Sanofi; consulting fees from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Novo Nordisk, GlaxoSmithKline plc., Medtronic, Merck, Pfizer, Portola, Sanofi; and honoraria for lectures from Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Novo Nordisk, and Bayer. PCH: DSMB member of Cerus Corporation project., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial demonstrated no overall difference in the composite primary endpoint and the secondary endpoints of cardiovascular (CV) death/myocardial infarction or all-cause mortality between an initial invasive or conservative strategy among participants with chronic coronary disease and moderate or severe myocardial ischemia. Detailed cause-specific death analyses have not been reported., Methods: We compared overall and cause-specific death rates by treatment group using Cox models with adjustment for pre-specified baseline covariates. Cause of death was adjudicated by an independent Clinical Events Committee as CV, non-CV, and undetermined. We evaluated the association of risk factors and treatment strategy with cause of death., Results: Four-year cumulative incidence rates for CV death were similar between invasive and conservative strategies (2.6% vs 3.0%; hazard ratio [HR] 0.98; 95% CI [0.70-1.38]), but non-CV death rates were higher in the invasive strategy (3.3% vs 2.1%; HR 1.45 [1.00-2.09]). Overall, 13% of deaths were attributed to undetermined causes (38/289). Fewer undetermined deaths (0.6% vs 1.3%; HR 0.48 [0.24-0.95]) and more malignancy deaths (2.0% vs 0.8%; HR 2.11 [1.23-3.60]) occurred in the invasive strategy than in the conservative strategy., Conclusions: In International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, all-cause and CV death rates were similar between treatment strategies. The observation of fewer undetermined deaths and more malignancy deaths in the invasive strategy remains unexplained. These findings should be interpreted with caution in the context of prior studies and the overall trial results., (Copyright © 2022. Published by Elsevier Inc.)

Importance: Clinical events adjudication is pivotal for generating consistent and comparable evidence in clinical trials. The methodology of event adjudication is evolving, but research is needed to develop best practices and spur innovation., Observations: A meeting of stakeholders from regulatory agencies, academic and contract research organizations, pharmaceutical and device companies, and clinical trialists convened in Chicago, IL, for Clinical Events Classification (CEC) Summit 2018 to discuss key topics and future directions. Formal studies are lacking on strategies to optimize CEC conduct, improve efficiency, minimize cost, and generally increase the speed and accuracy of the event adjudication process. Major challenges to CEC discussed included ensuring rigorous quality of the process, identifying safety events, standardizing event definitions, using uniform strategies for missing information, facilitating interactions between CEC members and other trial leadership, and determining the CEC's role in pragmatic trials or trials using real-world data. Consensus recommendations from the meeting include the following: (1) ensure an adequate adjudication infrastructure; (2) use negatively adjudicated events to identify important safety events reported only outside the scope of the primary endpoint; (3) conduct further research in the use of artificial intelligence and digital/mobile technologies to streamline adjudication processes; and (4) emphasize the importance of standardizing event definitions and quality metrics of CEC programs., Conclusions and Relevance: As novel strategies for clinical trials emerge to generate evidence for regulatory approval and to guide clinical practice, a greater understanding of the role of the CEC process will be critical to optimize trial conduct and increase confidence in the data generated., Competing Interests: Declaration of competing interest Sharma: reports receiving support from the Canada Institute for Health Research – 175095; Fonds de Recherche Santé Quebec (FRSQ) Junior 1 clinician scholars program, Alberta Innovates Health Solution, European Society of Cardiology young investigator grant, Roche Diagnostics, Boehringer-Ingelheim, Novartis, and Takeda. Mahaffey: disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Gibson: no relevant disclosures. Hicks: no relevant disclosures. Alexander: no disclosures reported. Ali: no disclosures reported. Chaitman: grants from National Heart, Lung and Blood Institute, Department of Defense, and personal fees from Merck, NovoNordisk, Sanofi, Lilly, Johnson and Johnson, Daiichi Sankyo, Tricida, Relypsa, Imbria, and Xylocor for DSMB/CEC work within 3 years and outside the submitted manuscript. Held: Institutional research grants from AstraZeneca, Pfizer, GlaxoSmithKline. Advisory board for AstraZeneca, Boehringer Ingelheim, Coala Life. Hlatky: no disclosures reported. Jones: research grants from Abbott, AstraZeneca, Bayer, Luitpold, Merck, Boehringer Ingelheim, National Institutes of Health, Patient Centered Outcomes Research Institute. Mehran: no disclosures reported. Menon: no disclosures reported. Rockhold: no relevant disclosures. Seltzer: no relevant disclosures. Spitzer: no relevant disclosures. Wilson: no disclosures reported. Lopes: disclosures can be viewed at https://scholars.duke.edu/person/renato.lopes., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known., Methods: We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute-sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction were ascertained., Results: Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer-determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to ≤5 at 101 (35.1%) laboratories, >5 to ≤10 at 34 (11.8%) laboratories, and >10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays., Conclusions: There is substantial hospital-level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications for both the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To determine whether sex-based differences exist in clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in patients with stable coronary artery disease., Background: A prior pre-specified unadjusted analysis from COURAGE showed that women randomized to PCI had a lower rate of death or myocardial infarction during a median 4.6-year follow-up with a trend for interaction with respect to sex., Methods: We analyzed outcomes in 338 women (15%) and 1949 men (85%) randomized to PCI plus OMT versus OMT alone after adjustment for relevant baseline characteristics., Results: There was no difference in treatment effect by sex for the primary end point (death or myocardial infarction; HR, 0.89; 95% CI, 0.77-1.03 for women and HR, 1.02, 95% CI 0.96-1.10 for men; P for interaction = .07). Although the event rate was low, a trend for interaction by sex was nonetheless noted for hospitalization for heart failure, with only women, but not men, assigned to PCI experiencing significantly fewer events as compared to their counterparts receiving OMT alone (HR, 0.59; 95% CI, 0.40-0.84, P < .001 for women and HR, 0.86; 95% CI, 0.74-1.01, P = .47 for men; P for interaction = .02). Both sexes randomized to PCI experienced significantly reduced need for subsequent revascularization (HR, 0.72; 95% CI, 0.62-0.83, P < .001 for women; HR, 0.84; 95% CI, 0.79-0.89, P < .001 for men; P for interaction = .02) with evidence of a sex-based differential treatment effect., Conclusion: In this adjusted analysis of the COURAGE trial, there were no significant differences in treatment effect on major outcomes between men and women. However, women assigned to PCI demonstrated a greater benefit as compared to men, with a reduction in heart failure hospitalization and need for future revascularization. These exploratory observations require further prospective study., (Copyright © 2015. Published by Elsevier Inc.)

Background: Different classes of glucose-lowering medications have been associated with varying risks of myocardial infarction and cardiovascular death, but their effect on angina is unknown. Therefore, we sought to determine the association of different glucose-lowering medication classes with angina frequency and nitroglycerin (NTG) use., Methods: We performed a secondary, observational analysis of the TERISA multinational trial, which evaluated the antianginal effect of ranolazine versus placebo in patients with type 2 diabetes mellitus, documented coronary disease, and a 3-month history of stable angina. Patients recorded angina and NTG use in a daily dairy for 3 weeks prior to randomization, to establish their baseline angina burden for the trial. We then examined the association of different glucose-lowering medication classes with baseline angina and NTG use using multivariable linear regression., Results: Among 952 patients enrolled, 494 were taking metformin, 504 taking a sulfonylurea, 186 taking insulin, 29 taking DPP-4 inhibitors, 22 taking other glucose-lowering medications, and 68 were diet-controlled only. After adjustment for demographic and clinical factors, patients taking versus not taking sulfonylureas had 1.02 more episodes of angina and used 0.93 more doses of NTG per week (P = .002 and .011, respectively). The weekly angina burden or NTG use was not different for those taking versus not taking metformin (P > .7 for both). Patients taking versus not taking insulin had 0.83 more episodes of angina and used 1.40 more NTG doses per week, increases evident only in those taking insulin without concomitant metformin (Pinteraction < .05 for both)., Conclusion: Different classes of glucose-lowering medications were associated with varying angina burden in patients with type 2 diabetes mellitus and stable coronary disease. Patients taking sulfonylureas or insulin had more angina and used more NTG, while metformin was not associated with angina burden. Given the increasing prevalence of glucose abnormalities in patients with coronary disease, a better understanding of the relationship between glucose-lowering medications and angina is needed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Ranolazine reduces the frequency of angina and use of sublingual nitroglycerin (SL NTG) in stable angina patients with type 2 diabetes (T2DM). Because pre-clinical data suggest that myocardial late sodium current (INaL), the target of ranolazine, is increased by hyperglycemia, we investigated whether the efficacy of ranolazine was influenced by glycemic control., Methods: TERISA was a multinational, randomized, double-blind trial of ranolazine vs. placebo in patients with T2DM and stable angina. Anginal episodes and SL NTG use were recorded daily in an electronic diary. Health status was evaluated at baseline and 8weeks post-randomization using the Seattle Angina Questionnaire (SAQ). The interaction between baseline HbA1c and treatment effect was tested across endpoints using analysis of covariance models, with HbA1c as a continuous variable with restricted cubic splines., Results: The study included 913 patients, with mean age 63.6years, 39% women, mean T2DM duration 7.4years, and mean HbA1c of 7.3%. Heterogeneity of efficacy by HbA1c was observed for the primary endpoint of angina frequency (Pinteraction = .027), the key secondary endpoint of SL NTG use (Pinteraction = .030), SAQ angina frequency (Pinteraction = .001), and SAQ treatment satisfaction (Pinteraction = .025) with greater efficacy of ranolazine in those with higher HbA1c values, increasing continuously from HbA1c levels >6.5%., Conclusion: Among patients with T2DM and stable angina, the therapeutic benefits of ranolazine were greater in those with higher HbA1c values. These data suggest that ranolazine is particularly beneficial in patients with stable angina who have suboptimally controlled T2DM., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: It is unknown if baseline angiographic findings can be used to estimate residual risk of patients with chronic stable angina treated with both optimal medical therapy (OMT) and protocol-assigned or symptom-driven percutaneous coronary intervention (PCI)., Methods: Death, myocardial infarction (MI), and hospitalization for non-ST-segment elevation acute coronary syndrome were adjudicated in 2,275 COURAGE patients. The number of vessels diseased (VD) was defined as the number of major coronary arteries with ≥50% diameter stenosis. Proximal left anterior descending, either isolated or in combination with other disease, was also evaluated. Depressed left ventricular ejection fraction (LVEF) was defined as ≤50%. Cox regression analyses included these anatomical factors as well as interaction terms for initial treatment assignment (OMT or OMT + PCI)., Results: Percutaneous coronary intervention and proximal left anterior descending did not influence any outcome. Death was predicted by low LVEF (hazard ratio [HR] 1.86, CI 1.34-2.59, P < .001) and VD (HR 1.45, CI 1.20-1.75, P < .001). Myocardial infarction and non-ST-segment elevation acute coronary syndrome were predicted only by VD (HR 1.53, CI 1.30-1.81 and HR 1.24, CI 1.06-1.44, P = .007, respectively)., Conclusions: In spite of OMT and irrespective of protocol-assigned or clinically driven PCI, LVEF and angiographic burden of disease at baseline retain prognostic power and reflect residual risk for secondary ischemic events., (© 2013.)

Background: The COURAGE trial reported similar clinical outcomes for patients with stable ischemic heart disease (SIHD) receiving optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI). The current post hoc substudy analysis examined the relationship between baseline stress myocardial ischemia and clinical outcomes based on randomized treatment assignment., Methods: A total of 1,381 randomized patients (OMT n = 699, PCI + OMT n = 682) underwent baseline stress myocardial perfusion single-photon emission computed tomographic imaging. Site investigators interpreted the extent of ischemia by the number of ischemic segments using a 6-segment myocardial model. Patients were divided into those with no to mild (<3 ischemic segments) and moderate to severe ischemia (≥ 3 ischemic segments). Cox proportional hazards models were calculated to assess time to the primary end point of death or myocardial infarction., Results: At baseline, moderate to severe ischemia occurred in more than one-quarter of patients (n = 468), and the incidence was comparable in both treatment groups (P = .36). The primary end point, death or myocardial infarction, was similar in the OMT and PCI + OMT treatment groups for no to mild (18% and 19%, P = .92) and moderate to severe ischemia (19% and 22%, P = .53, interaction P value = .65). There was no gradient increase in events for the overall cohort with the extent of ischemia., Conclusions: From the COURAGE trial post hoc substudy, the extent of site-defined ischemia did not predict adverse events and did not alter treatment effectiveness. Currently, evidence supports equipoise as to whether the extent and severity of ischemia impact on therapeutic effectiveness., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Observational analyses and short-term randomized trials have suggested that statins reduce occurrence or recurrence of atrial fibrillation (AF). We tested the hypothesis that long-term treatment with high-dose atorvastatin reduces occurrence of AF in patients with prior stroke or transient ischemic attack., Methods: We examined development of new AF in the SPARCL trial that compared atorvastatin 80 mg daily with placebo in 4,731 patients with prior stroke or transient ischemic attack. Patients who had chronic or paroxysmal AF or were taking medications for treatment or prophylaxis of AF at the time of enrollment were excluded. Atrial fibrillation was identified from electrocardiograms submitted to a blinded central electrocardiographic laboratory and from investigators' adverse event reports., Results: Patients were followed up for a median of 4.8 years, corresponding to >20,000 patient-years of observation with a median of 5 electrocardiograms per patient. The primary efficacy measure, the time from randomization to first occurrence of new AF, did not differ between treatment groups. By intention to treat, there were 139 cases of new AF in the atorvastatin group and 122 cases in the placebo group, corresponding to incidence rates of 1.32 and 1.14 cases per 100 patient-years observation (hazard ratio 1.15, 95% CI 0.90-1.46, P = .26). On-treatment analysis yielded similar findings, with incidence rates of 1.26 and 1.01 cases per 100 patient-years observation in the atorvastatin and placebo groups, respectively (hazard ratio 1.25, 95% CI 0.94-1.67, P = .12)., Conclusion: High-dose atorvastatin does not prevent development of AF in patients with prior stroke or transient ischemic attack., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background: Despite contemporary therapies for acute coronary syndrome (ACS), morbidity and mortality remain high. Low levels of high-density lipoprotein (HDL) cholesterol are common among patients with ACS and may contribute to ongoing risk. Strategies that raise levels of HDL cholesterol, such as inhibition of cholesterol ester transfer protein (CETP), might reduce risk after ACS. Dal-OUTCOMES is a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces cardiovascular morbidity and mortality in patients with recent ACS., Design: The study will randomize approximately 15,600 patients to receive daily doses of dalcetrapib 600 mg or matching placebo, beginning 4 to 12 weeks after an index ACS event. There are no prespecified boundaries for HDL cholesterol levels at entry. Other elements of care, including management of low-density lipoprotein cholesterol, are to follow best evidence-based practice. The primary efficacy measure is time to first occurrence of coronary heart disease death, nonfatal acute myocardial infarction, unstable angina requiring hospital admission, resuscitated cardiac arrest, or atherothrombotic stroke. The trial will continue until 1,600 primary end point events have occurred, all evaluable subjects have been followed for at least 2 years, and 80% of evaluable subjects have been followed for at least 2.5 years., Summary: Dal-OUTCOMES will determine whether CETP inhibition with dalcetrapib, added to current evidence-based care, reduces cardiovascular morbidity and mortality after ACS.

The population of patients with advanced coronary artery disease (CAD) is growing as a result of the aging of the general population, the extensive use of revascularization, and the efficacy of therapies that have prolonged the survival of patients with severe atherosclerosis. Patients with symptomatic CAD survive to a point where little else can be done to relieve their angina. Despite an anticipated growth in the number of patients with this condition within the next few decades, advanced CAD receives relatively little attention by the medical and research communities. As a result, the scope of the disease is not well defined, its coverage in guidelines from professional associations is limited, and few new medical options are available. In response to this, a group of experts from different fields were brought together at a meeting held December 4 to 5, 2006. This document has been developed as a 2-part article. In the first part, the contemporary and emerging therapies for advanced CAD were reviewed. The present part reviews the current status of understanding of advanced CAD, the limits of contemporary therapies, and the difficulties in and barriers to the development of new treatments.

The following report is based on a working group meeting about advanced coronary artery disease for patients with refractory ischemia who cannot receive revascularization. The aims were to review currently available treatment strategies, define unmet clinical needs, explore clinical trial design issues, and identify promising novel therapeutic targets and approaches for patients with chronic ischemia. The Working Group brought together medical experts in the management of refractory angina with representatives from regulatory agencies, Centers for Medicare and Medicaid Services, and industry. The meeting began with presentations reviewing the limitations of the current medical therapies and revascularization strategies and focused on lessons learned from past therapeutic attempts to optimize outcomes and on what are considered to be the most promising new approaches. Perspectives from clinical experts and from regulatory agencies were juxtaposed against needs and concerns of industry regarding development of new therapeutic strategies. This report presents the considerations and conclusions of the meeting on December 4-5, 2006. This document has been developed as a 2-part article, with contemporary and emerging therapies for advanced coronary artery disease reviewed first. Trial design, end points, and regulatory issues will be discussed in the second part of the article.

Background: Major improvements in medical therapy and percutaneous coronary intervention (PCI) for coronary heart disease have occurred during the past decade, but no randomized trial has compared these 2 strategies for the "hard" clinical end points of death or myocardial infarction nor have earlier studies incorporated the use of coronary stents and aggressive multifaceted medical therapy during long-term follow-up., Methods: The COURAGE trial is a multicenter study of patients with documented myocardial ischemia and angiographically confirmed single or multivessel coronary artery disease who are randomized to a strategy of PCI plus intensive medical therapy or intensive medical therapy alone. Medical therapy in both groups is guideline-driven and includes: aspirin, clopidogrel, simvastatin (low-density lipoprotein cholesterol target 60-85 mg/dL), long-acting metoprolol and/or amlodipine, lisinopril or losartan, and long-acting nitrates, as well as lifestyle interventions. The primary end point is a composite of all-cause mortality or acute myocardial infarction, and there will be 85% power to detect an absolute 4.6% (relative 22%) difference between strategies. The principal hypothesis is that PCI plus aggressive medical therapy (projected event rate 16.4%) will be superior to aggressive medical therapy alone (projected event rate 21%) during a 2.5- to 7-year (median of 5 years) follow-up., Conclusions: COURAGE is the largest prospective randomized trial of PCI versus intensive medical therapy to date and will define the incremental benefits of PCI in the setting of contemporary optimal medical therapy for chronic coronary heart disease. A total of 2287 patients have been enrolled, and follow-up will conclude in June 2006.

Objective: To determine if the correlation between magnitude of creatine kinase-myocardial band release after coronary artery bypass surgery and 6-month mortality is comparable to that of patients admitted with an acute coronary syndrome., Methods: The GUARDIAN trial tested the efficacy of cariporide, an Na+/H+ exchange inhibitor, on reduction of myocardial ischemia or death in high-risk patients. We compared 6-month survival in a cohort of 2332 GUARDIAN patients scheduled for coronary artery bypass surgery at entry with 4233 acute coronary syndrome patients stratified by level of creatine kinase-myocardial band release. Cumulative 6-month survival by creatine kinase-myocardial band categories was performed using life table analysis, adjusting for variables known to impact prognosis using Cox regression., Results: The 6-month mortality rates for coronary artery bypass surgery patients with peak creatine kinase-myocardial band ratios of <1, > or =1 and <5, > or =5 and <10, and > or =10 upper limits of normal (ULN) were 5.8, 2.8, 5.9, and 12.0%, respectively (P <.0001). The 6-month mortality rates for acute coronary syndrome patients with peak creatine kinase-myocardial band ratios of <1, > or =1 and <5, > or =5 and <10, and > or =10 ULN were 6.3, 9.8, 10.0, and 12.3%, respectively (P <.0001). Patients with coronary artery bypass surgery or acute coronary syndrome had similar adjusted 6-month survival estimates at normal creatine kinase-myocardial band levels and when the creatine kinase-myocardial band level was > or =10 ULN. Patients with coronary artery bypass surgery had significantly better survival at intermediate enzyme levels (> or =1 and <10 ULN; P <.001)., Conclusions: Modest elevations of creatine kinase-myocardial band release (> or =1 and <10 ULN) after coronary artery bypass surgery are not associated with adverse 6-month survival, in contrast to that seen in acute coronary syndrome patients. Routine creatine kinase-myocardial band sampling should be considered in all higher-risk patients undergoing coronary artery bypass surgery procedures to identify the sizable cohort of patients with creatine kinase-myocardial band release > or =10 ULN; these patients may benefit from postoperative angiotensin-converting enzyme inhibitor and beta-blocker therapy. Newer cardioprotective agents that reduce the number of patients with marked creatine kinase-myocardial band release are currently being tested in large randomized controlled clinical trials.