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Importance: Abnormal cardiac metabolism contributes to the pathophysiology of advanced heart failure with reduced left ventricular ejection fraction (LVEF). Glucagon-like peptide 1 (GLP-1) agonists have shown cardioprotective effects in early clinical studies of patients with advanced heart failure, irrespective of type 2 diabetes status.Objective: To test whether therapy with a GLP-1 agonist improves clinical stability following hospitalization for acute heart failure.Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with established heart failure and reduced LVEF who were recently hospitalized. Patients were enrolled between August 2013 and March 2015 at 24 US sites.Interventions: The GLP-1 agonist liraglutide (n = 154) or placebo (n = 146) via a daily subcutaneous injection; study drug was advanced to a dosage of 1.8 mg/d during the first 30 days as tolerated and continued for 180 days.Main Outcomes and Measures: The primary end point was a global rank score in which all patients, regardless of treatment assignment, were ranked across 3 hierarchical tiers: time to death, time to rehospitalization for heart failure, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. Higher values indicate better health (stability). Exploratory secondary outcomes included primary end point components, cardiac structure and function, 6-minute walk distance, quality of life, and combined events.Results: Among the 300 patients who were randomized (median age, 61 years [interquartile range {IQR}, 52-68 years]; 64 [21%] women; 178 [59%] with type 2 diabetes; median LVEF of 25% [IQR, 19%-33%]; median N-terminal pro-B-type natriuretic peptide level of 2049 pg/mL [IQR, 1054-4235 pg/mL]), 271 completed the study. Compared with placebo, liraglutide had no significant effect on the primary end point (mean rank of 146 for the liraglutide group vs 156 for the placebo group, P = .31). There were no significant between-group differences in the number of deaths (19 [12%] in the liraglutide group vs 16 [11%] in the placebo group; hazard ratio, 1.10 [95% CI, 0.57-2.14]; P = .78) or rehospitalizations for heart failure (63 [41%] vs 50 [34%], respectively; hazard ratio, 1.30 [95% CI, 0.89-1.88]; P = .17) or for the exploratory secondary end points. Prespecified subgroup analyses in patients with diabetes did not reveal any significant between-group differences. The number of investigator-reported hyperglycemic events was 16 (10%) in the liraglutide group vs 27 (18%) in the placebo group and hypoglycemic events were infrequent (2 [1%] vs 4 [3%], respectively).Conclusions and Relevance: Among patients recently hospitalized with heart failure and reduced LVEF, the use of liraglutide did not lead to greater posthospitalization clinical stability. These findings do not support the use of liraglutide in this clinical situation.Trial Registration: clinicaltrials.gov Identifier: NCT01800968. [ABSTRACT FROM AUTHOR]

The clinical entities that comprise acute coronary syndromes (ACS)-ST-segment elevation myocardial infarction (STEMI), non-STEMI, and unstable angina-have been recognized as widespread causes of death and disability for more than a century. Seminal research in the past 50 years has led to important scientific and medical advances in our understanding of ACS. Rapid modernization of the developing world has led to a pandemic of coronary artery disease and its manifestation as ACS, with profound implications for personal, societal, and global health. Epidemiological studies have provided insight into the changing demographics of ACS, and highlighted the importance of modifiable risk factors and adherence to guideline-recommended therapy. [ABSTRACT FROM AUTHOR]

The article discusses the efficacy and safety of loop diuretics in treating acute decompensated heart failure (ADHF) in the U.S. The article states that ADHF has evolved as an essential clinical syndromes in the country due to its high incidence of morbidity and medical costs. It also notes that loop diuretics poses properties that maintains the safety and effectiveness of the treatment supported by different clinical studies.

In 1994, the Agency for Health Care Policy and Research sponsored the development of guidelines for diagnosing and managing patients with unstable angina. Since their publication, several important developments have occurred. The prognostic value of biochemical assays for cardiac-specific troponins T and I have been shown in many studies. The possible role for C-reactive protein in determining prognosis deserves further investigation. Substantial clinical benefits have been obtained with intravenous inhibitors of the platelet glycoprotein (GP) IIb-IIIa receptor (abciximab, eptifibatide, tirofiban) and with one of the low-molecular-weight heparins (enoxaparin). The therapeutic potential of other low-molecular-weight heparins, direct thrombin inhibitors, and oral GP IIb-IIIa inhibitors remains to be clarified. On the basis of this evidence, consideration should be given to measuring serum levels of a cardiac troponin (either T or I) and using intravenous GP IIb-IIIa inhibitors and low-molecular-weight heparin in the standard management of patients with unstable angina. [ABSTRACT FROM AUTHOR]

The article analyzes the contribution of the American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines to the quality of cardiac care in the U.S. The task force is recognized for developing guidelines related to cardiovascular disease. Also discussed are the results of a study on the effect of the ACC/AHA guidelines on the management of hypertension, coronary artery disease and heart failure.

There is a growing schism between general internal medicine and the medical subspecialties. The latter are functioning increasingly as categorical disease centers, such as cardiac or cancer centers, which involve subspecialists from several departments. These new "horizontal" organizational units are thought to enhance the effectiveness of patient care as well as the generation of resources, especially for research and training. However, subspecialists operating outside of the framework of training, accreditation, and standards established by internal medicine are at risk for being less effective in dealing with the "whole" patient. Further, the critical evaluation of clinical practices of subspecialists is greatly needed and is far more likely to be accomplished effectively within departments of internal medicine than in categorical disease centers. Therefore, although some strengthening of the new horizontal organizational units now seems appropriate, this process must not be allowed to erode the important integrating structure provided by internal medicine. [ABSTRACT FROM AUTHOR]

The article looks at the improvement in heart failure (HF) hospitalization rates among older people in the U.S. It references a study by J. Chen et al. published within the issue. The study involved fee-for-service Medicare beneficiaries with HF. African American men were observed to have lower hospitalization rates compared with their white counterparts. Some recommended measures to improve patient outcomes include treatment of subclinical congestion and correcting cardiac abnormalities.

The authors offer information on the Digitalis Investigation Group trial, organized and conducted by the National Heart, Lung, and Blood Institute and the U.S. Department of Veterans Affairs. The trial evaluated the efficacy of digoxin in reducing hospitalizations of patients with chronic heart failure and in sinus rhythm. However, they note that despite the trial findings, digoxin use has decreased in registries and clinical trials of heart failure. They call for the reexamination of the role of digoxin in acute heart failure syndromes.

Background: Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin.Objectives: This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy.Methods: All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis.Results: Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005).Conclusions: Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878). [ABSTRACT FROM AUTHOR]

The article discusses the development of the medical treatment for coronary heart disease in the U.S. It tackles the progress in cardioprotection and mentions the recommendations from several workshops in 2010. It also examines the advancement on the protection against myocardial ischema and reperfusion injury, noting on various cardioprotective strategies.

Background: When compared with warfarin, edoxaban significantly reduced cardiovascular mortality in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. We studied the possible reasons leading to this reduction.Methods: ENGAGE AF-TIMI 48 was a double-blind, double-dummy comparison of warfarin with 2 regimens of once-daily edoxaban in 21,105 patients with atrial fibrillation followed for 2.8 years (median). Causes of deaths in the intention-to-treat population were classified as cardiovascular (including fatal bleeding and ischemic stroke), malignancy, or noncardiovascular/nonmalignancy by an independent, blinded, clinical endpoint committee. Deaths also were adjudicated as directly due to bleeding (ie, fatal), or bleeding contributing to death, or neither.Results: There were 839 total deaths (4.35%/y) in the warfarin arm, compared with 773 (3.99%/y, P = .08) with the higher-dose edoxaban regimen, and 737 (3.80%/y, P = .006) with the lower-dose edoxaban regimen. No significant differences between treatments were observed in (1) any of the 3 most common causes of cardiovascular death (sudden cardiac, heart failure, ischemic stroke), (2) fatal malignancies, (3) other noncardiovascular death. There were 124 fatal bleeds, 65 with warfarin, significantly fewer with the higher-dose (n = 35, P = .003) and lower-dose (n = 24, P < .001) edoxaban regimens. There were 101 bleeding events with warfarin that were either fatal or that contributed to death. There were significantly fewer with the higher-dose (n = 59, P = .001) and lower-dose (n = 54, P < .001) edoxaban regimens.Conclusions: Fewer total and cardiovascular deaths were observed with edoxaban as compared with warfarin in the ENGAGE AF-TIMI 48 trial, and this predominantly resulted from the significantly lower rate of major bleeding with edoxaban. Edoxaban reduces mortality both directly (less fatal bleeding) and indirectly (fewer bleeding-related complications and interruptions in therapy after nonfatal bleeding). [ABSTRACT FROM AUTHOR]

Background: There are major differences in the organization of the health care systems in Canada and the United States. We hypothesized that these differences may be accompanied by differences in patient care. Methods: To test our hypothesis, we compared the treatment patterns for patients with acute myocardial infarction in 19 Canadian and 93 United States hospitals participating in the Survival and Ventricular Enlargement (SAVE) study, which tested the effectiveness of captopril in this population of patients after a myocardial infarction. Results: In Canada, 51 percent of the patients admitted to a participating coronary care unit had acute myocardial infarctions, as compared with only 35 percent in the United States (P<0.001). Despite the similar clinical characteristics of the 1573 U.S. patients and 658 Canadian patients participating in the study, coronary arteriography was more commonly performed in the United States than in Canada (in 68 percent vs. 35 percent, P<0.001), as were revascularization procedures before randomization (31 percent vs. 12 percent, P<0.001). During an average follow-up of 42 months, these procedures were also performed more commonly in the United States than in Canada. These differences were not associated with any apparent difference in mortality (22 percent in Canada and 23 percent in the United States) or rate of reinfarction (14 percent in Canada and 13 percent in the United States), but there was a higher incidence of activity-limiting angina in Canada than in the United States (33 percent vs. 27 percent, P<0.007). Conclusions: The threshold for the admission of patients to a coronary care unit or for the use of invasive diagnostic and therapeutic interventions in the early and late periods after an infarction is higher in Canada than in the United States. This is not associated with any apparent difference in the rate of reinfarction or survival, but is associated with a higher frequency of activity-limiting angina. (N Engl J Med 1993;328:779-84.) [ABSTRACT FROM AUTHOR]

Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM are reviewed. Longer term extension studies may help address questions related to the positioning of mavacamten in current oHCM management algorithms, interactions with background therapy, as well as the potential for disease modification beyond symptomatic relief of left ventricular outflow tract obstruction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background People living with HIV are at increased risk of developing diastolic dysfunction, heart failure, and sudden cardiac death, all of which have been characterized by higher levels of myocardial fibrosis. Transmethylamine-N-oxide (TMAO), a dietary gut metabolite, is linked to the development of myocardial fibrosis in animal models. However, it is unclear whether TMAO plays a role in the development of myocardial fibrosis in people living with HIV. Methods and Results The study population consisted of participants enrolled in the multisite cross-sectional study called CHART-HIV (Characterizing Heart Function on Anti-Retroviral Therapy). Participants underwent echocardiography, cardiac magnetic resonance imaging, biomarker analysis, and targeted assessment of gut-related circulating metabolites; diastolic dysfunction was determined by study-specific criteria. Multivariable linear regression models were performed to examine the relationship of gut-related metabolites with serum and imaging measures of myocardial fibrosis. Models were adjusted for traditional cardiovascular, inflammatory, and HIV-related risk factors. Diastolic dysfunction was present in 94 of 195 individuals (48%) in CHART-HIV; this cohort demonstrated higher prevalence of hypertension, hyperlipidemia, and chronic kidney disease as well as higher plasma levels of both TMAO and choline. TMAO levels were associated with parameters reflecting increased left ventricular filling pressures and with a marker of the innate immune system. TMAO levels correlated with diffuse myocardial fibrosis ( R =0.35; P <0.05) as characterized by myocardial extracellular volume fraction as well as biomarkers reflective of myocardial fibrosis. Conclusions In this study of people living with HIV, the gut metabolite TMAO was associated with underlying diffuse myocardial fibrosis and found to be a potential marker of early structural heart disease. The mechanistic role of the gut microbiome in HIV-associated cardiovascular disease warrants further investigation. Registration URL: https://clinicaltrials.gov; Unique identifier: NCT02860156.

Aims: The present study aimed to assess the association between left atrial (LA) structure and function and the risk for cardiovascular (CV) death or heart failure (HF) hospitalization in a population with atrial fibrillation (AF)., Methods and Results: In a prospective echocardiographic substudy of the Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study, 971 patients underwent transthoracic echocardiography. The associations between LA structure (LA volume index [LAVi]) and function (LA emptying fraction [LAEF] and LA expansion index [LAEi]) and risk for the composite endpoint of CV death or HF hospitalization, and its components, were assessed. Over a median follow-up of 2.5 years, 142 patients (14.6%) experienced CV death or HF hospitalization. Higher LAVi and lower LAEF and LAEi were each associated with a higher unadjusted risk for the composite outcome and its components. After adjustment for clinical and echocardiographic confounders, only measures of impaired LA function were predictive of the composite outcome (hazard ratio [HR] per 1 standard deviation [SD] decrease in LAEF: 1.35; 95% confidence interval [CI] 1.09-1.67 [P = 0.005]; HR per 1 SD decrease in LAEi: 1.34; 95% CI 1.06-1.69 [P = 0.012]). These findings were similar regardless of left ventricular ejection fraction, history of HF or whether patients were in AF or sinus rhythm at the time of the echocardiographic examination., Conclusions: In patients with AF, LA dysfunction was significantly associated with an increased risk for CV death or HF hospitalization and was more predictive of these outcomes than LA size. These parameters may help to identify AF patients at greatest risk for the development of HF., Clinical Trial Registration: ClinicalTrials.gov, NCT00781391., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers., Methods: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy., Results: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required., Conclusions: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

The prevalence of Type 2 diabetes mellitus (T2DM) has reached pandemic proportions. T2DM frequently causes macrovascular and/or microvascular pathologic changes and thereby increases the risks for the development of myocardial infarction, heart failure, stroke, renal failure, and reduced survival. This article describes the important interactions between T2DM, heart failure, and renal dysfunction, forming vicious circles. The interruption of these circles represents important therapeutic goals., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain., Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS 2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores., Results: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA 2 DS 2 -VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA 2 DS 2 -VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin., Conclusions: The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study., (Copyright © 2018. Published by Elsevier Inc.)

Background: Peri-operative management of anticoagulated patients with atrial fibrillation (AF) is challenging. To gain information on the peri-operative management of edoxaban, we compared outcomes in patients on warfarin or edoxaban enrolled in ENGAGE AF-TIMI 48 who underwent a surgery or invasive procedure., Methods: Data from patients undergoing their first surgery/procedure were analysed and results compared by anticoagulant (warfarin vs. higher- or lower-dose edoxaban regimen [HDER and LDER, respectively]). Patients were classified by procedural management: anticoagulant interrupted (last dose 4-10 days pre-procedure) or anticoagulant continued (last dose ≤ 3 days pre-procedure). Stroke/systemic embolism (SSE), major bleeding (MB), MB or clinically relevant non-MB (CRNMB) and death were assessed from 7 days pre- until 30 days post-procedure. The chi-square test was used to compare outcomes across treatment groups., Results: A total of 7,193 patients (34%) underwent surgery/procedure: 3,116 had anticoagulant interrupted, 4,077 had anticoagulant continued. Among patients on warfarin, HDER and LDER who had anticoagulant interrupted, rates of SSE were 0.6, 0.5 and 0.9% ( p  = 0.53), rates of MB were 1.0, 1.2 and 1.1% ( p  = 0.94) and rates of MB or CRNMB were 3.9, 4.2 and 3.6% ( p  = 0.78); among patients on warfarin, HDER and LDER who had anticoagulant continued, rates of SSE were 1.1, 0.7 and 0.9% ( p  = 0.51), rates of MB were 3.6, 2.6 and 2.4% ( p  = 0.13) and rates of MB or CRNMB were 8.5, 7.9 and 6.6% ( p  = 0.17)., Conclusion: In patients requiring surgery/procedure in ENGAGE AF-TIMI 48, peri-operative rates of SSE, MB and death were not significantly different in patients who received edoxaban or warfarin., Competing Interests: J.D.D. reports personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Sanofi, Daiichi Sankyo and Janssen, outside the submitted work.S.A.M., E.M.A. and L.T.G. report grants from Daiichi Sankyo, during the conduct of the study.M.F.M. is employed by Daiichi-Sankyo and led the edoxaban development program.C.T.R. reports grants and personal fees from Daiichi Sankyo, personal fees from Bayer, Boehringer Ingelheim and Portola, during the conduct of the study.J.I.W. reports grants from Daiichi Sankyo, during the conduct of the study, personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ionis Pharmaceuticals, Janssen, Novartis, Merck, Pfizer and Portola, outside the submitted work.For the work under consideration, E.B. reports grant support to his institution from Daiichi Sankyo. For outside the submitted work, E.B. reports grant support to his institution from Glaxo Smith Kline, Merck, Novartis, Duke University and Astra Zeneca; uncompensated consultancies and lectures with Merck, and Novartis; personal fees for consultancies from The Medicines Company and Theravance; and personal fees for lectures from Medscape.R.P.G. reports grants from Daiichi Sankyo, during the conduct of the study, grants and personal fees from Daiichi Sankyo, Bristol Myers Squibb, Pfizer, Portola and Boehringer Ingelheim, outside the submitted work., (Schattauer GmbH Stuttgart.)

Background: Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA)., Methods and Results: We examined the efficacy and safety of vorapaxar in the intended use population, considering 20,170 patients randomized in the multinational, double-blinded, placebo-controlled TRA 2°P-TIMI 50 trial. Of these, 16,897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70., Conclusions: In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long-term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding., Clinical Trial Registration: URL: clinicaltrials.gov Unique Identifier: NCT00526474., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objectives: The aims of this study were to assess the prognostic value of cardiac troponin I levels, measured with a new high-sensitivity assay, in low-risk patients with stable coronary artery disease (CAD) and to contrast its determinants and prognostic merit with that of high-sensitivity cardiac troponin T (hs-TnT)., Background: New, highly sensitive cardiac troponin assays permit evaluation of the association between troponin levels and outcomes in patients with stable CAD., Methods: High-sensitivity cardiac troponin I (hs-TnI) levels at baseline were assessed in 3,623 patients with stable CAD and preserved systolic function enrolled in the PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy) trial., Results: In total, 98.5% of patients had hs-TnI concentrations higher than the detection level (1.2 pg/ml). hs-TnI correlated moderately with hs-TnT (r = 0.44) and N-terminal pro-B-type natriuretic peptide (r = 0.39) but only weakly with age (r = 0.17) and estimated glomerular filtration rate (r = -0.11). During a median follow-up period of 5.2 years, 203 patients died of cardiovascular causes or were hospitalized for heart failure, and 209 patients had nonfatal myocardial infarctions. In analyses adjusting for conventional risk markers, N-terminal pro-B-type natriuretic peptide, and hs-TnT, hs-TnI levels in the fourth compared with the 3 lower quartiles were associated with the incidence of cardiovascular death or heart failure (hazard ratio: 1.84; 95% confidence interval: 1.30 to 2.61; p < 0.001). [corrected]. There was a [corrected] weaker association with nonfatal myocardial infarction (hazard ratio: 1.37; 95% confidence interval: 0.98 to 1.92; p = 0.066). [corrected]. In the same models, hs-TnT concentrations were associated with the incidence of cardiovascular death or heart failure but not of myocardial infarction., Conclusions: In patients with stable CAD, hs-TnI concentrations are associated with cardiovascular risk independently of conventional risk markers and hs-TnT. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]; NCT00000558)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The availability of more sensitive biomarkers of myonecrosis and a new classification system from the universal definition of myocardial infarction (MI) have led to evolution of the classification of MI. The prognostic implications of MI defined in the current era have not been well described., Methods and Results: We investigated the association between new or recurrent MI by subtype according to the European Society of Cardiology/American College of Cardiology/American Heart Association/World Health Federation Task Force for the Redefinition of MI Classification System and the risk of cardiovascular death among 13 608 patients with acute coronary syndrome in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). The adjusted risk of cardiovascular death was evaluated by landmark analysis starting at the time of the MI through 180 days after the event. Patients who experienced an MI during follow-up had a higher risk of cardiovascular death at 6 months than patients without an MI (6.5% versus 1.3%, P<0.001). This higher risk was present across all subtypes of MI, including type 4a (peri-percutaneous coronary intervention, 3.2%; P<0.001) and type 4b (stent thrombosis, 15.4%; P<0.001). After adjustment for important clinical covariates, the occurrence of any MI was associated with a 5-fold higher risk of death at 6 months (95% confidence interval 3.8-7.1), with similarly increased risk across subtypes., Conclusions: MI is associated with a significantly increased risk of cardiovascular death, with a consistent relationship across all types as defined by the universal classification system. These findings underscore the clinical relevance of these events and the importance of therapies aimed at preventing MI.

Objectives: Saxagliptin, a dipeptidyl peptidase 4 inhibitor, improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by increasing endogenous active, intact glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in response to food, which augments insulin secretion and decreases glucagon release., Research Design and Methods: SAVOR-TIMI 53 is a phase 4, randomized, double-blind, placebo-controlled trial conducted in 25 countries that is designed to evaluate the safety and efficacy of saxagliptin during long-term treatment of approximately 16,500 patients with T2DM. Eligible patients who are either treatment naive or on any background antidiabetic treatment (except incretin therapy) with history of established cardiovascular (CV) disease or multiple risk factors are randomized 1:1 to saxagliptin 5 mg QD (2.5 mg in subjects with moderate/severe renal impairment) or matching placebo, stratified by qualifying disease state. The primary end point is the composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke. The trial will continue until approximately 1,040 primary end points accrue, providing 85% power to identify a 17% relative reduction of the primary end point with saxagliptin versus placebo and 98% power to test for noninferiority of saxagliptin versus placebo (reject the upper limit of 95% CI for a hazard ratio <1.3 at a 1-sided α of .025)., Conclusion: SAVOR-TIMI 53 is testing the hypothesis that treatment with saxagliptin is safe and reduces CV events in high-risk patients with T2DM., (Copyright © 2011 Mosby, Inc. All rights reserved.)

TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients ≥75 years old and weighing <60 kg. This defined 3 clinically relevant groups of patients for use of prasugrel at the studied dose regimen: group I (core clinical cohort), group II (noncore cohort), and group III (contraindicated). We assessed clinical outcomes of patients within these cohorts in the TRITON-TIMI 38 trial. Survival analysis methods were used to compare outcomes by treatment assignment (prasugrel vs clopidogrel) and by cohort (groups I and II or III). Patients in group I (n = 10,804, 79%) treated with prasugrel had a clinically significant and robust decrease in the primary end point of cardiovascular death, myocardial infarction, or stroke (8.3 vs 11.0%, hazard ratio [HR] 0.74, 95% confidence interval 0.66 to 0.84, p <0.0001), whereas patients in group II (n = 2149, 16%) had limited efficacy (15.3% vs 16.3%, HR 0.94, 0.76 to 1.18, p = 0.61, p for interaction = 0.07). For Thrombolysis In Myocardial Infarction major bleeding not related to coronary artery bypass grafting, there were tendencies to higher rates with prasugrel in group I (1.9% vs 1.5%, HR 1.24, 0.91 to 1.69, p = 0.17) and group II (4.1% vs 3.4%, HR 1.23, 0.77 to 1.97, p = 0.40); however, the absolute difference was greater for group II. The net clinical outcome (all-cause death/myocardial infarction/stroke/Thrombolysis In Myocardial Infarction major bleeding) in group I patients was highly favorable (10.2% vs 12.5%, HR 0.80, 0.71 to 0.89, p <0.0001) and neutral in group II (19.5% vs 19.7%, HR 0.98, 0.81 to 1.20, p for interaction = 0.07). Patients in group III (n = 518, 4%) did poorly with regard to efficacy and safety. In TRITON-TIMI 38 patients without previous stroke, <75 years old, and weighing >60 kg had substantial decreases in ischemic events with prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of prasugrel and limit the risk of adverse outcomes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To investigate growth differentiation factor (GDF)-15 at hospital discharge for assessment of the risk of death, recurrent myocardial infarction (MI), and congestive heart failure, and to determination of whether these risks can be modified by statins., Methods and Results: GDF-15 is a transforming growth factor-β-related cytokine induced in response to tissue injury. GDF-15 concentration is associated with all-cause mortality in patients with acute coronary syndrome (ACS). We measured GDF-15 in 3501 patients after ACS, treated with moderate or intensive statin therapy in PROVE IT-TIMI 22. By using established cutoff points, GDF-15 (<1200, 1200-1800, and >1800 ng/L) was associated with 2-year risk of death or MI (5.7%, 8.1%, and 15.1%, respectively; P<0.001), death (P<0.001), MI (P<0.001), and congestive heart failure (P<0.001). After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, smoking, MI, qualifying event, renal function, B-type natriuretic peptide, and high-sensitivity C-reactive protein, GDF-15 was associated with the risk of death or MI (adjusted hazard ratio per ln increase GDF-15, 2.1 [95% CI, 1.6 to 2.9]; P<0.001), death (P<0.001), MI (P<0.001), and congestive heart failure (P<0.001). There was no significant interaction between GDF-15 and intensive statin therapy for the risk of death or MI (P=0.24 for the interaction)., Conclusions: GDF-15 is associated with recurrent events after ACS, independent of clinical predictors, B-type natriuretic peptide, and high-sensitivity C-reactive protein. This finding supports GDF-15 as a prognostic marker in ACS and investigation of other therapies that modify this risk.

This paper details the substance and recommendations arising from a meeting convened by the National Heart, Lung, and Blood Institute in August 2009, to assess the challenges and opportunities of emergency department management of acute heart failure syndrome (AHFS). The assembled faculty represented a large cross section of medical professionals spanning the medical management continuum of patients presenting with acute heart failure and included heart failure cardiologists, emergency physicians, laboratory medicine specialists, nurses, and bench scientists. Their recommendations include proposals regarding the design and conduct of emergency department-based clinical trials, suggestions regarding the development of improved methods for early detection and monitoring of AHFS, and potential needs for expanding translational and applied AHFS focused research and biotechnology. We anticipate that this review will serve as a starting point for future investigations across the spectrum of funding sources., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with acute coronary syndromes and planned percutaneous coronary intervention, the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) demonstrated that treatment with prasugrel versus clopidogrel was associated with reduced rates of cardiovascular death, MI, or stroke and an increased risk of major bleeding. We evaluated the cost-effectiveness of prasugrel versus clopidogrel from the perspective of the US healthcare system by using data from TRITON-TIMI 38., Methods and Results: Detailed resource use data were prospectively collected for all patients recruited from 8 countries (United States, Australia, Canada, Germany, Italy, Spain, United Kingdom, and France; n=3373 prasugrel, n=3332 clopidogrel). Hospitalization costs were estimated on the basis of diagnosis-related group and in-hospital complications. Cardiovascular medication costs were estimated by using net wholesale prices (clopidogrel=$4.62/d; prasugrel=$5.45/d). Life expectancy was estimated from in-trial cardiovascular and bleeding events with the use of statistical models of long-term survival from a similar population from the Saskatchewan Health Database. Over a median follow-up of 14.7 months, average total costs (including study drug) were $221 per patient lower with prasugrel (95% confidence interval, -759 to 299), largely because of a lower rate of rehospitalization involving percutaneous coronary intervention. Prasugrel was associated with life expectancy gains of 0.102 years (95% confidence interval, 0.030 to 0.180), primarily because of the decreased rate of nonfatal MI. Thus, compared with clopidogrel, prasugrel was an economically dominant treatment strategy. If a hypothetical generic cost for clopidogrel of $1/d is used, the incremental net cost with prasugrel was $996 per patient, yielding an incremental cost-effectiveness ratio of $9727 per life-year gained., Conclusions: Among acute coronary syndrome patients with planned percutaneous coronary intervention, treatment with prasugrel versus clopidogrel for up to 15 months is an economically attractive treatment strategy., Clinical Trial Registration: clinicaltrials.gov. Unique identifier: NCT00097591.

Background: TIMI (Thrombolysis in Myocardial Infarction) Risk Index (TRI) is a simple bedside score that predicts 30-day mortality in patients with ST-elevation myocardial infarction (MI). We sought to evaluate whether TRI was predictive of long-term mortality and clinical events., Methods: In the TIMI 2 trial, 3,153 patients (mean age 57 +/- 10 years, 82% men) were randomized to invasive (n = 1,583) versus conservative (n = 1,570) strategy postfibrinolysis with median follow-up of 3 years. TIMI Risk Index was divided into 5 groups. The primary end point was all-cause mortality. Secondary analyses included recurrent MI, congestive heart failure (CHF), and combined end points., Results: When compared with group 1, mortality in group 5 was more than 5-fold higher (hazard ratio [HR] 5.83, P < .0001) and was also increased in group 4 (HR 2.80, P < .0001) and group 3 (HR 1.96, P = .002) (c statistic 0.69). No difference was seen between groups 1 and 2 (P = .74). A similar increasing gradient effect was seen across TRI strata with group 5 having the highest risk for CHF (HR 4.13, P < .0001) and the highest risk for composite death/CHF (HR 4.35, P < .0001) over group 1. There was no difference in recurrent MI between the groups (P = .22). After controlling for other risk indicators, the relationship between TRI and mortality remained significant: group 5, HR 4.11, P < .0001; group 4, HR 2.14, P = .0009; group 3, HR 1.69, P = .02. When stratified by TRI groups, no differences in mortality or composite death/MI were found between treatment strategies., Conclusions: The simple TRI can predict increased long-term mortality, CHF, and composite death/CHF.

The American College of Cardiology and American Heart Association have updated their guidelines for the management of non-ST-segment-elevation acute coronary syndrome for the first time since 2002. In the interim, several important studies affecting choices of therapy potentially begun in the emergency department have been completed, and care patterns have changed and matured significantly. In this review, we present the new recommendations that are pertinent to emergency medicine practice and comment on their potential implementation into an evidence-based, multidisciplinary approach to the evaluation and management of this challenging patient population.

In this perspective, I trace my experiences with the ASCI, beginning in 1952, when as a medical student I attended my first meeting, until 1975, when I completed my term as president of the Society. I focus attention on the sociological aspects of the Atlantic City meetings and the critically important role these meetings played in the evolution of academic medicine during the third quarter of the 20th century.

Objectives: The purpose of this research was to evaluate the Thrombolysis In Myocardial Infarction risk index (TRI) to characterize the risk of death among patients with non-ST-segment elevation myocardial infarction (NSTEMI)., Background: The TRI, calculated from baseline age, systolic pressure, and heart rate, was established in patients with ST-segment elevation myocardial infarction (STEMI) and is predictive of mortality. Patients presenting with NSTEMI are increasing compared to STEMI and constitute a group with varied risk., Methods: The TRI was calculated in 337,192 patients from the National Registry of Myocardial Infarction with NSTEMI. Values and outcomes were compared with 153,486 patients with STEMI classified by reperfusion status. Comparisons of baseline characteristics and clinical outcomes stratified by TRI were made., Results: There was a graded relationship between the TRI and mortality in patients with NSTEMI with a >30-fold difference in mortality rates between lowest and highest deciles (p < 0.0001). The index showed good discrimination (c = 0.73). Overall mortality in the group with NSTEMI was higher (10.9%) than patients with STEMI treated with (6.6%) but lower than for STEMI patients not receiving reperfusion therapy (18.7%). The higher risk in comparison to patients with STEMI treated with reperfusion therapy was explained largely by the higher-risk profile of the population with NSTEMI., Conclusions: There is a graded relationship between TRI and mortality in patients with NSTEMI. This simple risk index provides important information about mortality in patients across the spectrum of myocardial infarction, STEMI and NSTEMI. Early identification of NSTEMI patients who are at high risk of in-hospital mortality may provide clinicians with important information for initial triage and treatment.

Objectives: We sought to evaluate a simple risk index based on age and vital signs in a community sample of patients with ST-segment elevation myocardial infarction (STEMI)., Background: A simple risk index based on age and vital signs (heart rate x [age/10](2)/systolic blood pressure) developed from patients with STEMI accurately predicts mortality in clinical trials of fibrinolysis. The application of such a tool in an unselected population is necessary to evaluate its utility in clinical practice., Methods: To evaluate the Thrombolysis In Myocardial Infarction (TIMI) risk index for routine practice, we tested it in the National Registry of Myocardial Infarction (NRMI)-3 and -4. The risk index was evaluated as a continuous variable in patients with STEMI from NRMI and in subgroups based on age and reperfusion status., Results: A total of 153,486 patients with STEMI were eligible. As anticipated, STEMI patients in NRMI had a higher risk index profile, as compared with those in the clinical trial (median 26.9 vs. 20, p < 0.0001). Classification of NRMI patients with STEMI into risk groups revealed a significant graded relationship with mortality (0.9% to53.2%, p(trend) < 0.0001, c statistic 0.79). The discriminatory capacity of the risk index was particularly strong in the 81,679 patients receiving reperfusion therapy (0.6% to60%, p(trend) < 0.0001, c statistic 0.81). For the 71,807 patients not receiving reperfusion therapy, a strong graded relationship remained (1.9% to 52.2%, p(trend) < 0.0001, c statistic 0.71). Among the elderly, although the distribution of scores was shifted toward higher risk, the performance remained (0% to 53.1%, p(trend)< 0.0001, c statistic 0.71)., Conclusions: A simple risk index from baseline clinical variables routinely obtained at the first patient encounter predicted mortality in a large unselected heterogeneous group of patients with STEMI.

Impaired coronary artery blood flow and left anterior descending (LAD) artery culprit location are angiographic variables that have been associated with poorer outcomes after fibrinolytic administration in patients with acute myocardial infarction (AMI). We hypothesized that culprit lesion location in the proximal portion of the culprit artery would also be associated with poorer clinical outcomes compared with a mid or distal location. Lesion location and clinical outcomes were evaluated in 2,488 patients from the Thrombolysis In Myocardial Infarction (TIMI) 4, 10A, 10B, and 14 trials. Proximal lesions were located before or at the first major branch of the parent artery, mid lesions were between the first and the second major branches, and all other lesions were classified as distal. Proximal lesions were associated with a higher incidence of in-hospital death or recurrent AMI compared with mid or distal lesions (10.5% [n = 478] vs 6.1% [n = 1,498] vs 3.7% [n = 511], p <0.001), and they were associated with a higher rate of in-hospital death (6.7% [n = 478] vs 3.2% [n = 1,498] vs 2.5% [n = 511], p = 0.001). In a multiple logistic regression model adjusting for TIMI flow grade, age, gender, and pulse, the planimetered distance from the ostium to the LAD culprit lesion was associated with 30-day death or recurrent AMI (odds ratio 0.79 per centimeter increase in distance down the artery, p = 0.01). Proximal culprit lesion location is associated with an increased risk of adverse outcomes after fibrinolytic administration, which is likely due to a larger area of subtended myocardium. In patients with a LAD culprit lesion, proximal lesion location is a multivariate correlate of adverse outcomes even after adjustment for coronary blood flow and other covariates.

The unstable angina pectoris (UAP) classification proposed by Braunwald in 1989, although often used, has never been validated in a large, prospective multicenter study in which all subgroups of patients were included. Patients with UAP or non-ST-elevation myocardial infarction (NSTEMI) were enrolled in the Thrombolysis In Myocardial Ischemia III Registry and classified according to the Braunwald classification for UAP. Clinical end points were compared at 6 weeks and 1 year. Of 3,318 patients, those with primary UAP had lower rates of recurrent myocardial infarction (MI) or death when compared with patients with secondary UAP and post-MI UAP at 6 weeks (4.1% vs 6.4% vs 13.4%, respectively; p <0.001) and 1 year (9.7% vs 16.7% vs 19.7%; p <0.001). Recurrent ischemia at 6 weeks followed the same gradient (13.2% vs 18.5% vs 20.8%; p <0.001). Patients with secondary UAP had similar extent of disease at angiography as primary UAP. Patients with nonresting UAP had lower rates of death or MI than patients with UAP at rest (3.0% vs 5.6%, p = 0.011 at 6 weeks, and 8.2% vs 12.5%, p = 0.004 at 1 year). Patients with ST-segment deviation and those who had received prior antianginal medical treatment also had worse outcomes. Thus, the Braunwald classification of UAP predicts prognosis with secondary UAP, post-MI UAP, and patients with pain at rest who have a higher risk for death or recurrent cardiac events. Given their high risk for adverse events, patients with secondary UAP should be treated aggressively.

Background: In two large secondary prevention trials of pravastatin, risk reduction was not significant in participants who had low baseline LDL-C concentrations (that is, <125 mg/dL). We conducted exploratory analyses of participant characteristics, lipid risk factors, and risk reduction in this group., Methods and Results: Among 13 173 participants with coronary heart disease (CHD), 2607 had baseline LDL-C <125 mg/dL. Those with LDL-C <125 compared with > or =125 mg/dL were more likely to be diabetic (15% versus 9%), hypertensive (46 versus 41%), and male (89% versus 83%); they had higher triglycerides (169 versus 154 mg/dL), lower HDL-C (36.5 versus 38 mg/dL), and similar body mass index (27 kg/m2); and pravastatin lowered their LDL-C by 36 mg/dL (32%) versus 45 mg/dL (29%). During 5.8-year (mean) follow-up, HDL-C and triglycerides were both significantly stronger predictors of recurrent CHD events in participants with LDL-C <125 than > or =125 mg/dL. In diabetic participants with low LDL-C, pravastatin decreased CHD events from 34% to 22% (relative risk, 0.56; 95% CI, 0.37 to 0.83; P=0.004), significantly different from the effect in nondiabetic participants with low LDL-C (P interaction, 0.005) (event rate, 21%; relative risk, 1.06 [95% CI, 0.89 to 1.27]). There were trends toward risk reduction in smokers and in those with low HDL-C, <40 mg/dL., Conclusions: Among patients with CHD who have low LDL-C, diabetics have much higher subsequent CHD event rates than do nondiabetics. Pravastatin reduced the event rate in diabetics to that of nondiabetic participants. The results also suggest enhanced therapeutic potential for improving HDL-C and triglycerides in patients with CHD who have low LDL-C concentrations.