Ten-Year Mortality in the WISE Study (Women's Ischemia Syndrome Evaluation).

BACKGROUND: The WISE study (Women's Ischemia Syndrome Evaluation) was a prospective cohort study of 936 clinically stable symptomatic women who underwent coronary angiography to evaluate symptoms and signs of ischemia. Long-term mortality data for such women are limited. METHODS AND RESULTS: Obstructive coronary artery disease (CAD) was defined as ≥50% stenosis on angiography by core laboratory. We conducted a National Death Index search to assess the mortality of women who were alive at their final WISE contact date. Death certificates were obtained. All deaths were adjudicated as cardiovascular or noncardiovascular by a panel of WISE cardiologists masked to angiographic data. Multivariate Cox proportional hazards regression was used to identify significant independent predictors of mortality. At baseline, mean age was 58±12 years; 176 (19%) were non-white, primarily black; 25% had a history of diabetes mellitus, 59% hypertension, 55% dyslipidemia, and 59% had a body mass index ≥30. During a median follow-up of 9.5 years (range, 0.2-11.5 years), a total of 184 (20%) died. Of these, 115 (62%) were cardiovascular deaths; 31% of all cardiovascular deaths occurred in women without obstructive CAD (<50% stenosis). Independent predictors of mortality were obstructive CAD, age, baseline systolic blood pressure, history of diabetes mellitus, history of smoking, elevated triglycerides, and estimated glomerular filtration rate. CONCLUSIONS: Among women referred for coronary angiography for signs and symptoms of ischemia, 1 in 5 died from predominantly cardiac pathogeneses within 9 years of angiographic evaluation. A majority of the factors contributing to the risk of death seem to be modifiable by existing therapies. Of note, 1 in 3 of the deaths in this cohort occurred in women without obstructive CAD, a condition often considered benign and without guideline-recommended treatments. Clinical trials are needed to provide treatment guidance for the group without obstructive CAD.

Sudden Cardiac Death in Women With Suspected Ischemic Heart Disease, Preserved Ejection Fraction, and No Obstructive Coronary Artery Disease: A Report From the Women's Ischemia Syndrome Evaluation Study.

BACKGROUND: Sudden cardiac death (SCD) is often the first presentation of ischemic heart disease; however, there is limited information on SCD among women with and without obstructive coronary artery disease (CAD). We evaluated SCD incidence in the WISE (Women's Ischemia Syndrome Evaluation) study. METHODS AND RESULTS: Overall, 904 women with suspected ischemic heart disease with preserved ejection fraction and core laboratory coronary angiography were followed for outcomes. In case of death, a death certificate and/or a physician or family narrative of the circumstances of death was obtained. A clinical events committee rated all deaths as cardiovascular or noncardiovascular and as SCD or non-SCD. In total, 96 women (11%) died over a median of 6 years (maximum: 8 years). Among 65 cardiovascular deaths, 42% were SCD. Mortality per 1000 person-hours increased linearly with CAD severity (no CAD: 5.8; minimal: 15.9; obstructive: 38.6; P<0.0001). However, the proportion of SCD was similar across CAD severity: 40%, 58%, and 38% for no, minimal, and obstructive CAD subgroups, respectively (P value not significant). In addition to traditional risk factors (age, diabetes mellitus, smoking), a history of depression (P=0.018) and longer corrected QT interval (P=0.023) were independent SCD predictors in the entire cohort. Corrected QT interval was an independent predictor of SCD in women without obstructive CAD (P=0.033). CONCLUSIONS: SCD contributes substantially to mortality in women with and without obstructive CAD. Corrected QT interval is the single independent SCD risk factor in women without obstructive CAD. In addition to management of traditional risk factors, these data indicate that further investigation should address mechanistic understanding and interventions targeting depression and corrected QT interval in women.

Aortic flow conditions predict ejection efficiency in the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE).

BACKGROUND: The Windkessel model of the cardiovascular system, both in its original wind-chamber and flow-pipe form, and in its electrical circuit analog has been used for over a century to modeled left ventricular ejection conditions. Using parameters obtained from aortic flow we formed a Flow Index that is proportional to the impedance of such a "circuit". We show that the impedance varies with ejection fraction (EF) in a manner characteristic of a resonant circuit with multiple resonance points, with each resonance point centrally located in a small range of EF values, i.e., corresponding to multiple contiguous EF bands. METHODS: Two target populations were used: (I) a development group comprising male and female subjects (n=112) undergoing cardiovascular magnetic resonance (CMR) imaging for a variety of cardiac conditions. The Flow Index was developed using aortic flow data and its relationship to left ventricular EF was shown. (II) An illustration group comprised of female subjects from the Women's Ischemia Syndrome Evaluation (WISE) (n=201) followed for 5 years for occurrence of major adverse cardiovascular events (MACE). Flow data was not available in this group but since the Flow Index was related to the EF we noted the MACE rate with respect to EF. RESULTS: The EFs of the development population covered a wide range (9%-76%) traversing six Flow Index resonance bands. Within each Flow Index resonance band the impedance varied from highly capacitive at the lower range of EF through minimal impedance at resonance, to highly inductive at the higher range of EF, which is characteristic of a resonant circuit. When transitioning from one EF band to a higher band, the Flow Index made a sudden transition from highly inductive to capacitive impedance modes. MACE occurred in 26 (13%) of the WISE (illustration) population. Distance in EF units (Deltacenter) from the central location between peaks of MACE activity was derived from EF data and was predictive of MACE rate with an area under the receiver operator curve of 0.73. Of special interest, Deltacenter was highly predictive of MACE in the sub-set of women with EF >60% (AUC 0.79) while EF was no more predictive than random chance (AUC 0.48). CONCLUSIONS: A Flow Index that describes impedance conditions of left ventricular ejection can be calculated using data obtained completely from the ascending aorta. The Flow Index exhibits a periodic variation with EF, and in a separate illustration population the occurrence of MACE was observed to exhibit a similar periodic variation with EF, even in cases of normal EF.

Use of bio-informatics assessment schema (BIAS) to improve diagnosis and prognosis of myocardial perfusion data: results from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE).

BACKGROUND: We introduce an algorithmic approach to optimize diagnostic and prognostic value of gated cardiac single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) modalities in women with suspected myocardial ischemia. The novel approach: bio-informatics assessment schema (BIAS) forms a mathematical model utilizing MPI data and cardiac metrics generated by one modality to predict the MPI status of another modality. The model identifies cardiac features that either enhance or mask the image-based evidence of ischemia. For each patient, the BIAS model value is used to set an appropriate threshold for the detection of ischemia. METHODS: Women (n=130), with symptoms and signs of suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two different modalities: gated SPECT and MR. To determine perfusion status, MR data were evaluated qualitatively (MRIQL) and semi-quantitatively (MRISQ) while SPECT data were evaluated using conventional clinical criteria. Evaluators were masked to results of the alternate modality. These MPI status readings were designated "original". Two regression models designated "BIAS" models were generated to model MPI status obtained with one modality (e.g., MRI) compared with a second modality (e.g., SPECT), but importantly, the BIAS models did not include the primary Original MPI reading of the predicting modality. Instead, the BIAS models included auxiliary measurements like left ventricular chamber volumes and myocardial wall thickness. For each modality, the BIAS model was used to set a progressive threshold for interpretation of MPI status. Women were then followed for 38±14 months for the development of a first major adverse cardiovascular event [MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for heart failure]. Original and BIAS-augmented perfusion status were compared in their ability to detect coronary artery disease (CAD) and for prediction of MACE. RESULTS: Adverse events occurred in 14 (11%) women and CAD was present in 13 (10%). There was a positive correlation of maximum coronary artery stenosis and BIAS score for MRI and SPECT (P<0.001). Receiver operator characteristic (ROC) analysis was conducted and showed an increase in the area under the curve of the BIAS-augmented MPI interpretation of MACE vs. the original for MRISQ (0.78 vs. 0.54), MRIQL (0.78 vs. 0.64), SPECT (0.82 vs. 0.63) and the average of the three readings (0.80±0.02 vs. 0.60±0.05, P<0.05). CONCLUSIONS: Increasing values of the BIAS score generated by both MRI and SPECT corresponded to the increasing prevalence of CAD and MACE. The BIAS-augmented detection of ischemia better predicted MACE compared with the Original reading for the MPI data for both MRI and SPECT.

Pore Water Collection, Analysis and Evolution: The Need for Standardization.

Investigating the ecological impacts of contaminants released into the environment requires integration of multiple lines of evidence. Collection and analysis of interstitial water is an often-used line of evidence for developing benthic exposure estimates in aquatic ecosystems. It is a well-established principle that chemical and toxicity data on interstitial water samples should represent in-situ conditions; i.e., sample integrity must be maintained throughout the sample collection process to avoid alteration of the in-situ geochemical conditions. Unfortunately, collection and processing of pore water is not standardized to address possible geochemical transformations introduced by atmospheric exposure. Furthermore, there are no suitable benchmarks (ecological or human health) against which to evaluate adverse effects from chemicals in pore water; i.e., empirical data is lacking on the toxicity of inorganic contaminants in sediment interstitial water. It is clear that pore water data is best evaluated by considering the bioavailability of trace elements and the partitioning of contaminants between the aqueous and solid phases. It is also evident that there is a need for sediment researchers and regulatory agencies to collaborate in developing a standardized approach for sediment/pore water collection and data evaluation. Without such guidelines, the number of different pore water collection and extraction techniques will continue to expand, and investigators will continue to evaluate potentially questionable data by comparison to inappropriate criteria.

Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.

IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.

Natural attenuation of coal combustion waste in river sediments.

The weathering of coal combustion products (CCPs) in a lotic environment was assessed following the Tennessee Valley Authority (Kingston, TN) fly ash release of 2008 into surrounding rivers. Sampled materials included stockpiled ash and sediment collected from 180 to 880 days following the release. Total recoverable concentrations of heavy metals and metalloids in sediment were measured, and percent ash was estimated visually or quantified by particle counts. Arsenic and selenium in sediment were positively correlated with percent ash. For samples collected 180 days after the release, total concentrations of trace elements downstream of the release were greater than reference levels but less than concentrations measured in stockpiled ash. Total concentrations of trace elements remained elevated in ash-laden sediment after almost 2.5 years. A sequential extraction procedure (SEP) was used to speciate selected fractions of arsenic, copper, lead, nickel, and selenium in decreasing order of bioavailability. Concentrations of trace elements in sequentially extracted fractions were one to two orders of magnitude lower than total recoverable trace elements. The bulk of sequentially extractable trace elements was associated with iron-manganese oxides, the least bioavailable fraction of those measured. By 780 days, trace element concentrations in the SEP fractions approached reference concentrations in the more bioavailable water soluble, ion exchangeable, and carbonate-bound fractions. For each trace element, the percentage composition of the bioavailable fractions relative to the total concentration was calculated. These SEP indices were summed and shown to significantly decrease over time. These results document the natural attenuation of leachable trace elements in CCPs in river sediment as a result of the loss of bioavailable trace elements over time.

Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy.

Low-density lipoprotein cholesterol (LDL-C) levels are significantly associated with atherosclerotic cardiovascular disease (ASCVD) risk, and studies using interventions that lower LDL-C levels have been shown to reduce the risk of ASCVD events and mortality. Statin treatment is the current first-line therapy for lowering LDL-C and reducing ASCVD risk. However, many patients are still unable to reach recommended LDL-C goals on maximally tolerated statin therapy. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. The aim of this phase 3 study is to evaluate the efficacy of 12 weeks of subcutaneous evolocumab (vs placebo) administered every 2 weeks or every month in combination with a statin in patients with hypercholesterolemia and mixed dyslipidemia. This study will also provide comparative efficacy, safety, and tolerability data between evolocumab and ezetimibe when added to background atorvastatin therapy.

Left Ventricular Energy Model Predicts Adverse Events in Women With Suspected Myocardial Ischemia: Results From The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study.

OBJECTIVES: To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia. BACKGROUND: The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown. METHODS: Women (n=227, mean age 59±12 years, range 31-86), with symptoms of myocardial ischemia, underwent myocardial perfusion imaging (MPI) assessment for regional perfusion defects along with measurement of ventricular volumes separately by gated Single Photon Emission Computed Tomography (SPECT) (n= 207) and magnetic resonance imaging (MRI) (n=203). During follow-up (40±17 months), time to first major adverse cardiovascular event (MACE, death, myocardial infarction or hospitalization for congestive heart failure) was analyzed using MRI and gated SPECT variables. RESULTS: Adverse events occurred in 31 (14%). Multivariable Cox models were formed for each modality: IEU and wall thickness by MRI (Chi-squared 34, p<0.005) and IEU and systolic blood pressure by gated SEPCT (Chi-squared 34, p<0.005). The models remained predictive after adjustment for age, disease history and Framingham risk score. For each Cox model, patients were categorized as high-risk if the model hazard was positive and not high-risk otherwise. Kaplan-Meier analysis of time to MACE was performed for high-risk vs. not high-risk for MR (log rank 25.3, p<0.001) and gated SEPCT (log rank 18.2, p<001) models. CONCLUSIONS: Among women with suspected myocardial ischemia a high internal energy utilization has higher prognostic value than either a low EF or the presence of a myocardial perfusion defect assessed using two independent modalities of MR or gated SPECT.

AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). METHODS AND RESULTS: As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively (P<0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively (P<0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33, P<0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. CONCLUSIONS: AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient's atherogenic lipid profile.

Sex differences in presentation and outcome among patients with type 2 diabetes and coronary artery disease treated with contemporary medical therapy with or without prompt revascularization: a report from the BARI 2D Trial (Bypass Angioplasty Revascularization Investigation 2 Diabetes).

OBJECTIVES: This study evaluated differences in outcome among women and men enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial. BACKGROUND: Women and men with coronary artery disease have different clinical presentations and outcomes that might be due to differences in management. METHODS: We compared baseline variables, study interventions, and outcomes between women and men enrolled in the BARI 2D trial and randomized to aggressive medical therapy alone or aggressive medical therapy with prompt revascularization. RESULTS: At enrollment, women were more likely than men to have angina (67% vs. 58%, p < 0.01) despite less disease on angiography (Myocardial Jeopardy Index 41 ± 24 vs. 46 ± 24, p < 0.01; number of significant lesions 2.3 ± 1.7 vs. 2.8 ± 1.8, p < 0.01). Over 5 years, no sex differences were observed in BARI 2D study outcomes after adjustment for difference in baseline variables (death/myocardial infarction/cerebrovascular accident: hazard ratio: 1.11, 99% confidence interval [CI]: 0.85 to 1.44). However, women reported more angina than men (adjusted odds ratio: 1.51, 99% CI: 1.21 to 1.89, p < 0.0001) and had lower scores for the Duke Activity Status Index (adjusted beta coefficient: -1.58, 99% CI: -2.84 to -0.32, p < 0.01). CONCLUSIONS: There were no sex differences in death, myocardial infarction, or cerebrovascular accident among patients enrolled in the BARI 2D trial. However, compared with men, women had more symptoms and less anatomic disease at baseline, with persistence of higher angina rates and lower DASI scores after 5 years of medical therapy with or without prompt revascularization. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI 2D]; NCT00006305).

Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: insights from the SOLVD Treatment trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). METHODS: In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤ 35% and serum creatinine level ≤ 2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m(2)). RESULTS: Overall, during 35 months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74-0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73-1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69-0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66-0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70-0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04 mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7 mm Hg, both) and serum potassium (mean increase, 0. /L, both). CONCLUSIONS: Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD.

Improved diagnosis and prognosis using Decisions Informed by Combining Entities (DICE): results from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE).

OBJECTIVES: To introduce an algorithmic approach to improve the interpretation of myocardial perfusion images in women with suspected myocardial ischemia. BACKGROUND: Gated single photon emission computed tomography (SPECT) and magnetic resonance (MR) myocardial perfusion imaging (MPI) approaches have relatively poor diagnostic and prognostic value in women with suspected myocardial ischemia. Here we introduce an approach: Decisions Informed by Combining Entities (DICE) that forms a mathematical model utilizing MPI and cardiac dimensions generated by one modality to predict the perfusion status of another modality. The effect of the model is to systematically incorporate cardiac metrics that influence the interpretation of perfusion images, leading to greater consistency in designation of myocardial perfusion status between studies. METHODS: Women (n=213), with suspected myocardial ischemia, underwent MPI assessment for regional perfusion defects using two modalities: gated SPECT (n=207) and MR imaging (n=203). To determine perfusion status, MR data were evaluated qualitatively and semi-quantitatively while SPECT data were evaluated using conventional clinical criteria. These perfusion status readings were designated "Original". Four regression models were generated to model perfusion status obtained with one modality [e.g., semi-quantitative magnetic resonance imaging (MRI)] against another modality (e.g., SPECT) and a threshold applied (DICE modeling) to designate perfusion status as normal or low. The DICE models included perfusion status, left ventricular (LV) chamber volumes and myocardial wall thickness. Women were followed for 40±16 months for the development of first major adverse cardiovascular event (MACE: CV death, nonfatal myocardial infarction (MI) or hospitalization for congestive heart failure). Original and DICE perfusion status were compared in their ability to detect high-grade coronary artery disease (CAD) and for prediction of MACE. RESULTS: Adverse events occurred in 25 (12%) women and CAD was present in 34 (16%). In receiver-operator characteristic (ROC) analysis for CAD detection, the average area under the curve (AUC) for DICE vs. Original status was 0.77±0.03 vs. 0.70±0.03, P<0.01. Similarly, in Kaplan-Meier survival analysis the average log-rank statistic was higher for DICE vs. the Original readings (10.6±5.2 vs. 3.0±0.6, P<0.05). CONCLUSIONS: While two data sets are required to generate the DICE models no knowledge of follow-up results is needed. DICE modeling improved diagnostic and prognostic value vs. the Original interpretation of the myocardial perfusion status.

Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study.

BACKGROUND: LDL cholesterol (LDL-C) is a well established risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds LDL receptors, targeting them for degradation. We therefore assessed the efficacy, safety, and tolerability of AMG 145, a human monoclonal IgG2 antibody against PCSK9, in stable patients with hypercholesterolemia on a statin. METHODS: In a phase 2, dose-ranging study done in 78 centres in the USA, Canada, Denmark, Hungary, and Czech Republic, patients (aged 18-80 years) with LDL-C greater than 2·2 mmol/L on a stable dose of statin (with or without ezetimibe), were randomly assigned equally, through an interactive voice response system, to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or matching placebo every 2 weeks; or subcutaneous injections of AMG 145 280 mg, 350 mg, or 420 mg, or matching placebo every 4 weeks. Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules. The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01380730. FINDINGS: 631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n=79), 105 mg (n=79), or 140 mg (n=78), or matching placebo (n=78) every 2 weeks; or AMG 145 280 mg (n=79), 350 mg (n=79), and 420 mg (n=80), and matching placebo (n=79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41·8% to 66·1%; p<0·0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41·8% to 50·3%; p<0·0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening. INTERPRETATION: The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials. FUNDING: Amgen.

Diabetes mellitus and trends in hospital survival after myocardial infarction, 1994 to 2006: data from the national registry of myocardial infarction.

BACKGROUND: Patients with diabetes mellitus (DM) are at high risk for mortality after myocardial infarction (MI). Despite an overall trend of reduced mortality after MI, the mortality gap between MI patients with and without DM did not decrease over time in previous analyses. We assessed recent trends in hospital mortality for patients with MI according to DM status. METHODS AND RESULTS: We analyzed data from the National Registry of Myocardial Infarction, a contemporary registry of MI patients treated in 1964 hospitals, representing approximately one fourth of all US acute care hospitals. The study comprised 1734431 MI patients enrolled from 1994 to 2006, including 502315 (29%) with DM. Crude hospital mortality decreased in all patients between 1994 and 2006 but remained higher in patients with DM compared with those without DM throughout the study. The absolute difference in mortality between patients with and without DM significantly narrowed over time, from 15.6% versus 11.5% in 1994 to 8.0% versus 6.8% in 2006 (P<0.001 for DM × time interaction). The adjusted odds ratio for mortality associated with DM declined from 1.24 (95% confidence interval, 1.16-1.32) in 1994 to 1.08 (95% confidence interval, 0.99-1.19) in 2006 (P<0.001 for trend). The largest improvement in hospital mortality was observed in diabetic women (17.9% in 1994 versus 8.4% in 2006; P<0.001). CONCLUSIONS: The hospital mortality gap between MI patients with and without DM narrowed significantly from 1994 to 2006, with the greatest improvement observed in women with DM.

Clinical and angiographic risk stratification and differential impact on treatment outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. METHODS AND RESULTS: An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery-selected patients in the highest angiographic risk tertile (P=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P=0.010; hazard ratio=2.10; P=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. CONCLUSION: Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Atherosclerotic risk factors and their association with hospital mortality among patients with first myocardial infarction (from the National Registry of Myocardial Infarction).

Few studies have examined associations between atherosclerotic risk factors and short-term mortality after first myocardial infarction (MI). Histories of 5 traditional atherosclerotic risk factors at presentation (diabetes, hypertension, smoking, dyslipidemia, and family history of premature heart disease) and hospital mortality were examined among 542,008 patients with first MIs in the National Registry of Myocardial Infarction (1994 to 2006). On initial MI presentation, history of hypertension (52.3%) was most common, followed by smoking (31.3%). The least common risk factor was diabetes (22.4%). Crude mortality was highest in patients with MI with diabetes (11.9%) and hypertension (9.8%) and lowest in those with smoking histories (5.4%) and dyslipidemia (4.6%). The inclusion of 5 atherosclerotic risk factors in a stepwise multivariate model contributed little toward predicting hospital mortality over age alone (C-statistic = 0.73 and 0.71, respectively). After extensive multivariate adjustments for clinical and sociodemographic factors, patients with MI with diabetes had higher odds of dying (odds ratio [OR] 1.23, 95% confidence interval [CI] 1.20 to 1.26) than those without diabetes and similarly for hypertension (OR 1.08, 95% CI 1.06 to 1.11). Conversely, family history (OR 0.71, 95% CI 0.69 to 0.73), dyslipidemia (OR 0.62, 95% CI 0.60 to 0.64), and smoking (OR 0.85, 95% CI 0.83 to 0.88) were associated with decreased mortality (C-statistic = 0.82 for the full model). In conclusion, in the setting of acute MI, histories of diabetes and hypertension are associated with higher hospital mortality, but the inclusion of atherosclerotic risk factors in models of hospital mortality does not improve predictive ability beyond other major clinical and sociodemographic characteristics.

Differences in symptom presentation and hospital mortality according to type of acute myocardial infarction.

BACKGROUND: Chest pain/discomfort (CP) is the hallmark symptom of acute myocardial infarction (MI), but some patients with MI present without CP. We hypothesized that MI type (ST-segment elevation MI [STEMI] or non-STEMI [NSTEMI]) may be associated with the presence or absence of CP. METHODS: We investigated the association between CP at presentation and MI type, hospital care, and mortality among 1,143,513 patients with MI in the National Registry of Myocardial Infarction (NRMI) from 1994 to 2006. RESULTS: Overall, 43.6% of patients with NSTEMI and 27.1% of patients with STEMI presented without CP. For both MI type, patients without CP were older, were more frequently female, had more diabetes or history of heart failure, were more likely to delay hospital arrival, and were less likely to receive evidence-based medical therapies and invasive cardiac procedures. Multivariable analysis indicated that NSTEMI (vs STEMI) was the strongest predictor of atypical symptoms (adjusted odds ratio [95% CI], 1.93 [1.91-1.95]). Within the 4 CP/MI type categories, hospital mortality was highest for no CP/STEMI (27.8%), followed by no CP/NSTEMI (15.3%) and CP/STEMI (9.6%), and was lowest for CP/NSTEMI (5.4%). The adjusted odds ratio of mortality was 1.38 (1.35-1.41) for no CP (vs CP) in the STEMI group and 1.31 (1.28-1.34) in the NSTEMI group. CONCLUSIONS: Hospitalized patients with NSTEMI were nearly 2-fold more likely to present without CP than patients with STEMI. Patients with MI without CP were less quickly diagnosed and treated and had higher adjusted odds of hospital mortality, regardless of whether they had ST-segment elevation.

Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality.

CONTEXT: Women are generally older than men at hospitalization for myocardial infarction (MI) and also present less frequently with chest pain/discomfort. However, few studies have taken age into account when examining sex differences in clinical presentation and mortality. OBJECTIVE: To examine the relationship between sex and symptom presentation and between sex, symptom presentation, and hospital mortality, before and after accounting for age in patients hospitalized with MI. DESIGN, SETTING, AND PATIENTS: Observational study from the National Registry of Myocardial Infarction, 1994-2006, of 1,143,513 registry patients (481,581 women and 661,932 men). MAIN OUTCOME MEASURES: We examined predictors of MI presentation without chest pain and the relationship between age, sex, and hospital mortality. RESULTS: The proportion of MI patients who presented without chest pain was significantly higher for women than men (42.0% [95% CI, 41.8%-42.1%] vs 30.7% [95% CI, 30.6%-30.8%]; P < .001). There was a significant interaction between age and sex with chest pain at presentation, with a larger sex difference in younger than older patients, which became attenuated with advancing age. Multivariable adjusted age-specific odds ratios (ORs) for lack of chest pain for women (referent, men) were younger than 45 years, 1.30 (95% CI, 1.23-1.36); 45 to 54 years, 1.26 (95% CI, 1.22-1.30); 55 to 64 years, 1.24 (95% CI, 1.21-1.27); 65 to 74 years, 1.13 (95% CI, 1.11-1.15); and 75 years or older, 1.03 (95% CI, 1.02-1.04). Two-way interaction (sex and age) on MI presentation without chest pain was significant (P < .001). The in-hospital mortality rate was 14.6% for women and 10.3% for men. Younger women presenting without chest pain had greater hospital mortality than younger men without chest pain, and these sex differences decreased or even reversed with advancing age, with adjusted OR for age younger than 45 years, 1.18 (95% CI, 1.00-1.39); 45 to 54 years, 1.13 (95% CI, 1.02-1.26); 55 to 64 years, 1.02 (95% CI, 0.96-1.09); 65 to 74 years, 0.91 (95% CI, 0.88-0.95); and 75 years or older, 0.81 (95% CI, 0.79-0.83). The 3-way interaction (sex, age, and chest pain) on mortality was significant (P < .001). CONCLUSION: In this registry of patients hospitalized with MI, women were more likely than men to present without chest pain and had higher mortality than men within the same age group, but sex differences in clinical presentation without chest pain and in mortality were attenuated with increasing age.

Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease.

CONTEXT: Variants in the CYP2C19 gene influence the pharmacologic and clinical response to the standard 75-mg daily maintenance dose of the antiplatelet drug clopidogrel. OBJECTIVE: To test whether higher doses (up to 300 mg daily) improve the response to clopidogrel in the setting of loss-of-function CYP2C19 genotypes. DESIGN, SETTING, AND PATIENTS: ELEVATE-TIMI 56 was a multicenter, randomized, double-blind trial that enrolled and genotyped 333 patients with cardiovascular disease across 32 sites from October 2010 until September 2011. INTERVENTIONS: Maintenance doses of clopidogrel for 4 treatment periods, each lasting approximately 14 days, based on genotype. In total, 247 noncarriers of a CYP2C19*2 loss-of-function allele were to receive 75 and 150 mg daily of clopidogrel (2 periods each), whereas 86 carriers (80 heterozygotes, 6 homozygotes) were to receive 75, 150, 225, and 300 mg daily. MAIN OUTCOME MEASURES: Platelet function test results (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y(12) assays) and adverse events. RESULTS: With 75 mg daily, CYP2C19*2 heterozygotes had significantly higher on-treatment platelet reactivity than did noncarriers (VASP platelet reactivity index [PRI]: mean, 70.0%; 95% CI, 66.0%-74.0%, vs 57.5%; 95% CI, 55.1%-59.9%, and VerifyNow P2Y(12) reaction units [PRU]: mean, 225.6; 95% CI, 207.7-243.4, vs 163.6; 95% CI, 154.4-173.9; P < .001 for both comparisons). Among CYP2C19*2 heterozygotes, doses up to 300 mg daily significantly reduced platelet reactivity, with VASP PRI decreasing to 48.9% (95% CI, 44.6%-53.2%) and PRU to 127.5 (95% CI, 109.9-145.2) (P < .001 for trend across doses for both). Whereas 52% of CYP2C19*2 heterozygotes were nonresponders (≥230 PRU) with 75 mg of clopidogrel, only 10% were nonresponders with 225 or 300 mg (P < .001 for both). Clopidogrel, 225 mg daily, reduced platelet reactivity in CYP2C19*2 heterozygotes to levels achieved with standard clopidogrel, 75 mg, in noncarriers (mean ratios of platelet reactivity, VASP PRI, 0.92; 90% CI, 0.85-0.99, and PRU, 0.94; 90% CI, 0.84-1.04). In CYP2C19*2 homozygotes, even with 300 mg daily of clopidogrel, mean VASP PRI was 68.3% (95% CI, 44.9%-91.6%) and mean PRU, 287.0 (95% CI, 170.2-403.8). CONCLUSION: Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01235351.