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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 endpoint is a composite of all-cause death or recurrent MI through 30 days following randomization. Secondary endpoints 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 endpoints.Conclusions: The MINT trial will inform RBC transfusion practice in patients with acute MI. [ABSTRACT FROM AUTHOR]

Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown. The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA. Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia. Among 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2]). Among participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522) [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Several researchers have found that patients who undergo surgery on peripheral blood vessels are at increased risk of a heart attack. This observation has led some physicians to recommend that all candidates for surgery on peripheral blood vessels be screened for abnormalities in their coronary arteries using coronary angiography. This point of view is controversial, however. While the exercise stress test is useful in discovering defects in the coronary arteries in some patients, the test is often limited by the inability of the patients to tolerate the required level of exercise. In such cases, dipyridamole thallium scintigraphy may be useful. Thallium-201 is a radioactive isotope which, when injected, can be used to image blood flow. Dipyridamole is injected to mimic the effects of exercise, and hence point out defects in the circulation among patients who cannot undergo the exercise stress test. Dipyridamole thallium scintigraphy was used to screen 131 candidates for peripheral vascular surgery to determine if an abnormal scintigraph was an indicator of high risk for cardiac complications. Of the 131 candidates, 111 actually underwent the surgical procedures. Of the original candidates, 68 had a defect in the cardiac circulation distinguishable by means of dipyridamole thallium scintigraphy. Seven percent of these died or had myocardial infarction in the postoperative period, as compared with none in the group without defects seen on scintigraphy. On long-term follow-up, the risk of a serious cardiac event was 17 percent in the defect group and only six percent in the 'no apparent defect' group. Both differences were statistically significant. The results suggest that dipyridamole thallium scintigraphy may be useful in identifying high-risk patients for whom coronary artery surgery may be appropriate prior to peripheral vascular surgery, as well as low-risk patients for whom cardiac events are unlikely. (Consumer Summary produced by Reliance Medical Information, Inc.)

Myocardial infarction (MI, heart attack) is the deterioration of heart tissue due to the cessation of blood supply which may result from a blood clot obstructing one of the coronary arteries, the major vessels supplying blood to the heart. Thrombolytic agents, such as tissue plasminogen activator (t-PA), which break down blood clots may be useful in the treatment of MI. Thrombolysis in Myocardial Infarction (TIMI) phase II is a multicenter study of 228 patients with MI who were treated with t-PA within four hours after the onset of symptoms. Within 18 to 48 hours after thrombolytic therapy, these patients underwent percutaneous transluminal coronary angioplasty, a procedure in which a balloon attached to a catheter, or flexible tube, is inserted into the narrowed portion of a coronary vessel and inflated to enlarge the vessel. The estimated six-week, six-month, and one-year rates of death or MI were 9, 13, and 14 percent, respectively. Most of the cardiac events, such as recurrent MI, occurred early during the follow-up period. Continuing chest pain after t-PA treatment, a history of congestive heart failure, low blood pressure at initial evaluation, and hypertension, or abnormally high blood pressure, increased the risks of death or recurrent MI. Patient age and history of chest discomfort influenced future hospitalization or the frequency of procedures to revascularize, or restore blood flow to the heart. (Consumer Summary produced by Reliance Medical Information, Inc.)

Exercise testing and the electrocardiographic monitoring of ambulatory patients have demonstrated that many people develop the electrophysiological indications of myocardial ischemia (reduced blood supply to the heart muscle), i.e. ST depression, without developing pain. This myocardial ischemia without angina pectoris is called silent ischemia, and is less well studied than angina pectoris. While it is known that patients with angina are likely to fare better in the long term with coronary artery surgery than with medical treatment, it is uncertain what treatments are most appropriate for patients with silent myocardial ischemia. To evaluate the risks involved with silent ischemia, the cases of 404 patients with coronary artery disease were reviewed. Of these patients, 121 had silent ischemia, 124 had angina pectoris, and 159 had no signs of ischemia. In addition, 37 patients without coronary artery disease were included as controls. The results showed that the prognosis for patients with silent ischemia was related to the severity of the underlying coronary artery disease. Among patients with disease involving three vessels, those treated medically had only a 37 percent survival rate at seven years, in contrast with 83 percent for those who underwent surgical treatment. The study found that the presence of ischemia was a poor prognostic factor, regardless of whether the ischemia announced its presence through angina, or not. For the patients with silent ischemia, the survival could be significantly improved by coronary bypass surgery. (Consumer Summary produced by Reliance Medical Information, Inc.)

Following successful repair of heart vessels, a process known as angioplasty, early testing of the effects of exercise can be used for prognosis. This study examined patients who had heart surgery for single- or multivessel heart disease and who underwent an exercise test within thirty days of the operation. Changes in the electrocardiogram (ECG) were greater in patients with multivessel disease, indicating increased risk of further heart problems. Those patients experiencing chest pains, or angina, during or following exercise also had a higher incidence of cardiac events during the follow-up period. Abnormalities in the ECG following exercise testing can be used to predict subsequent heart problems in patients with multivessel heart disease. The test might have better prognostic value if it were performed several months after the operation, when the risk of re-blocking of the vessels is greater.

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. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to determine the relative utility of anatomic and ischemic burden of coronary artery disease for predicting outcomes. Background: Both anatomic burden and ischemic burden of coronary artery disease determine patient prognosis and influence myocardial revascularization decisions. When both measures are available, their relative utility for prognostication and management choice is controversial. Methods: A total of 621 patients enrolled in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial with baseline quantitative nuclear single-photon emission computed tomography (SPECT) and quantitative coronary angiography were studied. Several multiple regression models were constructed to determine independent predictors of the endpoint of death, myocardial infarction (MI) (excluding periprocedural MI) and non–ST-segment elevation acute coronary syndromes (NSTE-ACS). Ischemic burden during stress SPECT, anatomic burden derived from angiography, left ventricular ejection fraction, and assignment to either optimal medical therapy (OMT) + percutaneous coronary intervention (PCI) or OMT alone were analyzed. Results: In nonadjusted and adjusted regression models, anatomic burden and left ventricular ejection fraction were consistent predictors of death, MI, and NSTE-ACS, whereas ischemic burden and treatment assignment were not. There was a marginal (p = 0.03) effect of the interaction term of anatomic and ischemic burden for the prediction of clinical outcome, but separately or in combination, neither anatomy nor ischemia interacted with therapeutic strategy to predict outcome. Conclusions: In a cohort of patients treated with OMT, anatomic burden was a consistent predictor of death, MI, and NSTE-ACS, whereas ischemic burden was not. Importantly, neither determination, even in combination, identified a patient profile benefiting preferentially from an invasive therapeutic strategy. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657) [Copyright &y& Elsevier]

Abstract: Objectives: We evaluated inter-reader agreement of the ST-segment between two electrocardiogram (ECG) core laboratories. Background: Accurate measurement of the ST-segment is key to diagnosis and management of acute coronary syndromes (ACS). Clinical trials also rely on adherence to the pre-specified ECG eligibility criteria. Methods: 150 patients (100 ST-segment elevation (STE)-ACS, 50 non-STE-ACS) were selected. An experienced ECG reader from each laboratory measured ST-segment deviation on the baseline ECGs (nearest 0.1mm). Results: ∑ST-segment deviation showed excellent inter-reader agreement (R=0.965, intraclass correlation coefficient (ICC) 0.949, 95% CI (0.930–0.963)). Similar agreement was observed when ∑ST-segment elevation (∑STE) and ∑ST-segment depression (∑STD) were assessed separately. Better agreement was evident in STE-ACS cohort (ICC (95% CI): 0.968 (0.953–0.978, 0.969 (0.954–0.979), 0.931 (0.899–0.953)) compared to NSTE-ACS patients (ICC (95% CI): 0.860 (0.768–0.917), 0.816 (0.699–0.890), 0.753 (0.605–0.851) across measurement of ∑ST-segment deviation, ∑STE, and ∑STD. Conclusions: We demonstrated excellent agreement on ST-segment measurements between two experienced readers from two ECG core laboratories. [Copyright &y& Elsevier]

Background: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. Objective: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. Methods: We examined a prolonged QT interval corrected by using the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas. Results: Among 14,538 ARIC study participants, a prolonged QTFram predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42–2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14; 95% CI 1.10–1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07–1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts. Conclusions: A prolonged QT interval is associated with an increased risk of incident AF. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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 &y& Elsevier]

Objectives: The purpose of this explanatory analysis was to investigate the relationship between ST-segment depression and the rate-pressure product (RPP) during exercise to determine whether ranolazine''s mechanism of action was related to a reduction in myocardial oxygen demand or preservation of myocardial oxygen supply. Background: In patients with stable ischemic heart disease, ranolazine increases exercise duration and reduces maximal ST-segment depression while exerting minimal effects on heart rate and blood pressure, although its mechanism of action during exercise has not been investigated. Methods: Patients with stable ischemic heart disease (n = 191) were randomly allocated to a 4-period, double-blind, balanced Latin square crossover study to receive placebo, and ranolazine 500, 1,000, and 1,500 mg twice daily (bid) for 1 week each. Exercise treadmill tests were performed at baseline and at the end of each treatment period. The RPP and ST-segment depression were assessed before starting exercise, at each stage of exercise, and at maximal exercise. Results: Compared with placebo, ranolazine produced a dose-dependent reduction in ST-segment depression that became more marked as exercise-induced ischemia became more pronounced, associated with clinically minor decreases in heart rate and blood pressure. At 12-min exercise, the amount of ST-segment depression compared with placebo and controlled for RPP was reduced by 22.3% on ranolazine 500 mg bid (p = 0.137), by 35.4% on 1,000 mg bid (p = 0.005), and by 45.8% on 1,500 mg bid (p < 0.001). Conclusions: The progressive magnitude of ischemia reduction on ranolazine was proportionally more substantial than the minor reductions in heart rate or RPP, suggesting that ranolazine''s beneficial mechanism of action is most likely primarily due to an improvement in regional coronary blood flow in areas of myocardial ischemia. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Angiotensin-converting enzyme inhibition is not an effective antianginal therapy. Experimental data suggest that broader vasopeptidase inhibition may decrease the magnitude of demand-induced myocardial ischemia. A randomized, double-blind, placebo controlled parallel study evaluated omapatrilat, an inhibitor of angiotensin-converting enzyme and neutral endopeptidase. The primary objective was to compare maximum duration of exercise at peak plasma concentrations. Exercise treadmill studies were performed in 348 patients who had chronic angina at baseline and after 4 weeks of therapy with 80 mg/day omapatrilat or placebo. Safety data were collected and reported for all patients. Treadmill exercise duration at peak was significantly prolonged in the omapatrilat group compared with the placebo group (76.6 ± 84.2 vs 28.7 ± 82.2 seconds difference from baseline, p &#60;0.001). Similar statistically significant increases were seen in time to onset of level III/IV angina and time to onset of ≥0.1-mV ST-segment depression (p &#60;0.001). The significant improvements in exercise duration and measurements of myocardial ischemia were not sustained 20 to 28 hours after dosing. Omapatrilat was generally well tolerated in this predominantly normotensive population. The incidence of serious adverse events was 5.2% in the 2 groups. Thus, omapatrilat, an investigational vasopeptidase inhibitor, is effective in prolonging exercise duration and parameters of demand-induced myocardial ischemia in patients who have chronic angina at peak concentrations. The data confirm the proof of principle that broader vasopeptidase inhibition beyond angiotensin-converting enzyme inhibition is required to alleviate symptoms of chronic angina. [Copyright &y& Elsevier]

: ObjectivesThe primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose-response relationship of ranolazine, a potentially new anti-anginal compound, on symptom-limited exercise duration.: BackgroundFatty acids rise precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use.: MethodsPatients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations.: ResultsExercise duration at trough increased with ranolazine 500, 1,000, and 1,500 mg twice daily by 94, 103, and 116 s, respectively, all greater (p < 0.005) than the 70-s increase on placebo. Dose-related increases in exercise duration at peak and in times to 1 mm ST-segment depression at trough and peak and to angina at trough and peak were also demonstrated (all p < 0.005). Ranolazine had negligible effects on heart rate and blood pressure. One year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 ± 1.7%.: ConclusionsIn chronic angina patients, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied without clinically meaningful hemodynamic effects. One-year survival was not lower than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for chronic angina patients. [Copyright &y& Elsevier]

Examines the association between electrocardiographic (ECG) abnormalities after coronary revascularization and five-year cardiac mortality in randomized and registry patients. Frequency of postprocedural ECG abnormalities; Description of the study population; Adjusted relative risk of cardiac mortality.

It is clinically important to estimate the size of a myocardial infarction (MI) to predict patient prognosis, to determine the ability of a therapy to limit its size, and to evaluate its effect on left ventricular function. Various electrocardiographic methods have been used for these purposes but their accuracies have not been compared with each other using an identical reference population of anatomically measured infarcts. The capability of 4 electrocardiographic scoring methods (the Selvester score, the Minnesota code, the Novacode, and the Cardiac Infarction Injury Score) to estimate MI size was compared using anatomic MI size in a group of 100 deceased patients. All patients had a standard 12-lead electrocardiogram of sufficient quality to perform manual waveform measurements and without confounding factors such as ventricular hypertrophy, fascicular block, or bundle branch block. The location and size of the left ventricular infarction was measured postmortem using the anatomic method of Ideker et al. All methods' size estimates correlated best with anatomic MI size in the anterior location (r = 0.65 to 0.89). The Selvester score was superior in estimating the sizes of inferior (r = 0.70) and posterolateral (r = 0.74) infarcts. For multiple infarcts all methods performed poorly (r = 0.18 to 0.44). [ABSTRACT FROM AUTHOR]

Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported. Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management. ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management. ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference −3.5; 95% CI: −7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was −2.4%. Results were similar but less pronounced with FCR. The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522) [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (I NaL ), 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 8 weeks post-randomization using the Seattle Angina Questionnaire (SAQ). The interaction between baseline HbA 1c and treatment effect was tested across endpoints using analysis of covariance models, with HbA 1c as a continuous variable with restricted cubic splines. Results The study included 913 patients, with mean age 63.6 years, 39% women, mean T2DM duration 7.4 years, and mean HbA 1c of 7.3%. Heterogeneity of efficacy by HbA 1c was observed for the primary endpoint of angina frequency ( P interaction = .027), the key secondary endpoint of SL NTG use ( P interaction = .030), SAQ angina frequency ( P interaction = .001), and SAQ treatment satisfaction ( P interaction = .025) with greater efficacy of ranolazine in those with higher HbA 1c values, increasing continuously from HbA 1c levels >6.5%. Conclusion Among patients with T2DM and stable angina, the therapeutic benefits of ranolazine were greater in those with higher HbA 1c values. These data suggest that ranolazine is particularly beneficial in patients with stable angina who have suboptimally controlled T2DM. [ABSTRACT FROM AUTHOR]