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<div><h4>Biventricular pacing in patients with bradycardia and normal ejection fraction.</h4><i>Yu CM, Chan JY, Zhang Q, Omar R, ... Chan HC, Fung JW</i><br />BACKGROUND: Observational studies suggest that conventional right ventricular apical pacing may have a deleterious effect on left ventricular function. In this study, we examined whether biventricular pacing is superior to right ventricular apical pacing in preventing deterioration of left ventricular systolic function and cardiac remodeling in patients with bradycardia and a normal ejection fraction. <br /><b>Methods:</b><br/>In this prospective, double-blind, multicenter study, we randomly assigned 177 patients in whom a biventricular pacemaker had been successfully implanted to receive biventricular pacing (89 patients) or right ventricular apical pacing (88 patients). The primary end points were the left ventricular ejection fraction and left ventricular end-systolic volume at 12 months. <br /><b>Results:</b><br/>At 12 months, the mean left ventricular ejection fraction was significantly lower in the right-ventricular-pacing group than in the biventricular-pacing group (54.8+/-9.1% vs. 62.2+/-7.0%, P<0.001), with an absolute difference of 7.4 percentage points, whereas the left ventricular end-systolic volume was significantly higher in the right-ventricular-pacing group than in the biventricular-pacing group (35.7+/-16.3 ml vs. 27.6+/-10.4 ml, P<0.001), with a relative difference between the groups in the change from baseline of 25% (P<0.001). The deleterious effect of right ventricular apical pacing occurred in prespecified subgroups, including patients with and patients without preexisting left ventricular diastolic dysfunction. Eight patients in the right-ventricular-pacing group (9%) and one in the biventricular-pacing group (1%) had ejection fractions of less than 45% (P=0.02). There was one death in the right-ventricular-pacing group, and six patients in the right-ventricular-pacing group and five in the biventricular-pacing group were hospitalized for heart failure (P=0.74). <br /><b>Conclusions:</b><br/>In patients with normal systolic function, conventional right ventricular apical pacing resulted in adverse left ventricular remodeling and in a reduction in the left ventricular ejection fraction; these effects were prevented by biventricular pacing. (Centre for Clinical Trials number, CUHK_CCT00037.)<br /><br /><small>N Engl J Med: 26 Nov 2009; 361:2123-34</small></div>
Yu CM, Chan JY, Zhang Q, Omar R, ... Chan HC, Fung JW
N Engl J Med: 26 Nov 2009; 361:2123-34 | PMID: 19915220
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<div><h4>Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest.</h4><i>Nielsen N, Wetterslev J, Cronberg T, Erlinge D, ... Friberg H, the TTM Trial Investigators</i><br /><b>Background:</b><br/>Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. Methods In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. Results In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. <br /><b>Conclusions:</b><br/>In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916 .).<br /><br /><small>N Engl J Med: 17 Nov 2013; epub ahead of print</small></div>
Nielsen N, Wetterslev J, Cronberg T, Erlinge D, ... Friberg H, the TTM Trial Investigators
N Engl J Med: 17 Nov 2013; epub ahead of print | PMID: 24237006
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<div><h4>Trial of Continuous or Interrupted Chest Compressions during CPR.</h4><i>Nichol G, Leroux B, Wang H, Callaway CW, ... Ornato JP, ROC Investigators</i><br /><b>Background:</b><br/>During cardiopulmonary resuscitation (CPR) in patients with out-of-hospital cardiac arrest, the interruption of manual chest compressions for rescue breathing reduces blood flow and possibly survival. We assessed whether outcomes after continuous compressions with positive-pressure ventilation differed from those after compressions that were interrupted for ventilations at a ratio of 30 compressions to two ventilations. Methods This cluster-randomized trial with crossover included 114 emergency medical service (EMS) agencies. Adults with non-trauma-related cardiac arrest who were treated by EMS providers received continuous chest compressions (intervention group) or interrupted chest compressions (control group). The primary outcome was the rate of survival to hospital discharge. Secondary outcomes included the modified Rankin scale score (on a scale from 0 to 6, with a score of ≤3 indicating favorable neurologic function). CPR process was measured to assess compliance. Results Of 23,711 patients included in the primary analysis, 12,653 were assigned to the intervention group and 11,058 to the control group. A total of 1129 of 12,613 patients with available data (9.0%) in the intervention group and 1072 of 11,035 with available data (9.7%) in the control group survived until discharge (difference, -0.7 percentage points; 95% confidence interval [CI], -1.5 to 0.1; P=0.07); 7.0% of the patients in the intervention group and 7.7% of those in the control group survived with favorable neurologic function at discharge (difference, -0.6 percentage points; 95% CI, -1.4 to 0.1, P=0.09). Hospital-free survival was significantly shorter in the intervention group than in the control group (mean difference, -0.2 days; 95% CI, -0.3 to -0.1; P=0.004). <br /><b>Conclusions:</b><br/>In patients with out-of-hospital cardiac arrest, continuous chest compressions during CPR performed by EMS providers did not result in significantly higher rates of survival or favorable neurologic function than did interrupted chest compressions. (Funded by the National Heart, Lung, and Blood Institute and others; ROC CCC ClinicalTrials.gov number, NCT01372748 .).<br /><br /><small>N Engl J Med: 08 Nov 2015; epub ahead of print</small></div>
Nichol G, Leroux B, Wang H, Callaway CW, ... Ornato JP, ROC Investigators
N Engl J Med: 08 Nov 2015; epub ahead of print | PMID: 26550795
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<div><h4>Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis.</h4><i>Beardsley J, Wolbers M, Kibengo FM, Ggayi AM, ... Day JN, CryptoDex Investigators</i><br /><b>Background:</b><br/>Cryptococcal meningitis associated with human immunodeficiency virus (HIV) infection causes more than 600,000 deaths each year worldwide. Treatment has changed little in 20 years, and there are no imminent new anticryptococcal agents. The use of adjuvant glucocorticoids reduces mortality among patients with other forms of meningitis in some populations, but their use is untested in patients with cryptococcal meningitis. Methods In this double-blind, randomized, placebo-controlled trial, we recruited adult patients with HIV-associated cryptococcal meningitis in Vietnam, Thailand, Indonesia, Laos, Uganda, and Malawi. All the patients received either dexamethasone or placebo for 6 weeks, along with combination antifungal therapy with amphotericin B and fluconazole. Results The trial was stopped for safety reasons after the enrollment of 451 patients. Mortality was 47% in the dexamethasone group and 41% in the placebo group by 10 weeks (hazard ratio in the dexamethasone group, 1.11; 95% confidence interval [CI], 0.84 to 1.47; P=0.45) and 57% and 49%, respectively, by 6 months (hazard ratio, 1.18; 95% CI, 0.91 to 1.53; P=0.20). The percentage of patients with disability at 10 weeks was higher in the dexamethasone group than in the placebo group, with 13% versus 25% having a prespecified good outcome (odds ratio, 0.42; 95% CI, 0.25 to 0.69; P<0.001). Clinical adverse events were more common in the dexamethasone group than in the placebo group (667 vs. 494 events, P=0.01), with more patients in the dexamethasone group having grade 3 or 4 infection (48 vs. 25 patients, P=0.003), renal events (22 vs. 7, P=0.004), and cardiac events (8 vs. 0, P=0.004). Fungal clearance in cerebrospinal fluid was slower in the dexamethasone group. Results were consistent across Asian and African sites. <br /><b>Conclusions:</b><br/>Dexamethasone did not reduce mortality among patients with HIV-associated cryptococcal meningitis and was associated with more adverse events and disability than was placebo. (Funded by the United Kingdom Department for International Development and others through the Joint Global Health Trials program; Current Controlled Trials number, ISRCTN59144167 .).<br /><br /><small>N Engl J Med: 09 Feb 2016; 374:542-554</small></div>
Beardsley J, Wolbers M, Kibengo FM, Ggayi AM, ... Day JN, CryptoDex Investigators
N Engl J Med: 09 Feb 2016; 374:542-554 | PMID: 26863355
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<div><h4>Extended-release niacin or ezetimibe and carotid intima-media thickness.</h4><i>Taylor AJ, Villines TC, Stanek EJ, Devine PJ, ... Weissman NJ, Turco M</i><br />BACKGROUND: Treatment added to statin monotherapy to further modify the lipid profile may include combination therapy to either raise the high-density lipoprotein (HDL) cholesterol level or further lower the low-density lipoprotein (LDL) cholesterol level. <br /><b>Methods:</b><br/>We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol per liter, respectively) had been achieved. The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial. <br /><b>Results:</b><br/>The mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter (P < 0.001), and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per liter) (P < 0.001). Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima-media thickness over 14 months (P = 0.003), leading to significant reduction of both mean (P = 0.001) and maximal carotid intima-media thickness (P < or = 0.001 for all comparisons). Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness (R = -0.31, P < 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04 by the chi-square test). <br /><b>Conclusions:</b><br/>This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima-media thickness when combined with a statin and that niacin is superior to ezetimibe. (ClinicalTrials.gov number, NCT00397657.)<br /><br /><small>N Engl J Med: 26 Nov 2009; 361:2113-22</small></div>
Taylor AJ, Villines TC, Stanek EJ, Devine PJ, ... Weissman NJ, Turco M
N Engl J Med: 26 Nov 2009; 361:2113-22 | PMID: 19915217
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<div><h4>Effects of Medical Therapies on Retinopathy Progression in Type 2 Diabetes.</h4><i>The ACCORD Study Group and ACCORD Eye Study Group</i><br />BACKGROUND: We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. <br /><b>Methods:</b><br/>In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. <br /><b>Results:</b><br/>At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). <br /><b>Conclusions:</b><br/>Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 30 Jun 2010; epub ahead of print</small></div>
The ACCORD Study Group and ACCORD Eye Study Group
N Engl J Med: 30 Jun 2010; epub ahead of print | PMID: 20587587
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<div><h4>Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction.</h4><i>Redfield MM, Anstrom KJ, Levine JA, Koepp GA, ... Braunwald E, NHLBI Heart Failure Clinical Research Network</i><br /><b>Background:</b><br/>Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients. Methods In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). Results In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels. <br /><b>Conclusions:</b><br/>Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493 .).<br /><br /><small>N Engl J Med: 08 Nov 2015; epub ahead of print</small></div>
Redfield MM, Anstrom KJ, Levine JA, Koepp GA, ... Braunwald E, NHLBI Heart Failure Clinical Research Network
N Engl J Med: 08 Nov 2015; epub ahead of print | PMID: 26549714
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<div><h4>Childhood Obesity, Other Cardiovascular Risk Factors, and Premature Death.</h4><i>Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC</i><br />BACKGROUND: The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood. <br /><b>Methods:</b><br/>In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O\'odham Indian heritage. <br /><b>Results:</b><br/>There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24). <br /><b>Conclusions:</b><br/>Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes. Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 11 Feb 2010; 362:485-493</small></div>
Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC
N Engl J Med: 11 Feb 2010; 362:485-493 | PMID: 20147714
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<div><h4>A Randomized Trial of Intensive versus Standard Blood-Pressure Control.</h4><i>SPRINT Research Group</i><br /><b>Background:</b><br/>The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. Methods We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. Results At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). All-cause mortality was also significantly lower in the intensive-treatment group (hazard ratio, 0.73; 95% CI, 0.60 to 0.90; P=0.003). Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group. <br /><b>Conclusions:</b><br/>Among patients at high risk for cardiovascular events but without diabetes, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensive-treatment group. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01206062 .).<br /><br /><small>N Engl J Med: 08 Nov 2015; epub ahead of print</small></div>
SPRINT Research Group
N Engl J Med: 08 Nov 2015; epub ahead of print | PMID: 26551272
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<div><h4>Patient-Specific Induced Pluripotent Stem-Cell Models for Long-QT Syndrome.</h4><i>Moretti A, Bellin M, Welling A, Jung CB, ... Schömig A, Laugwitz KL</i><br />BACKGROUND: Long-QT syndromes are heritable diseases associated with prolongation of the QT interval on an electrocardiogram and a high risk of sudden cardiac death due to ventricular tachyarrhythmia. In long-QT syndrome type 1, mutations occur in the KCNQ1 gene, which encodes the repolarizing potassium channel mediating the delayed rectifier I(Ks) current. <br /><b>Methods:</b><br/>We screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene. We obtained dermal fibroblasts from two family members and two healthy controls and infected them with retroviral vectors encoding the human transcription factors OCT3/4, SOX2, KLF4, and c-MYC to generate pluripotent stem cells. With the use of a specific protocol, these cells were then directed to differentiate into cardiac myocytes. <br /><b>Results:</b><br/>Induced pluripotent stem cells maintained the disease genotype of long-QT syndrome type 1 and generated functional myocytes. Individual cells showed a "ventricular," "atrial," or "nodal" phenotype, as evidenced by the expression of cell-type-specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in "ventricular" and "atrial" cells derived from patients with long-QT syndrome type 1, as compared with cells from control subjects. Further characterization of the role of the R190Q-KCNQ1 mutation in the pathogenesis of long-QT syndrome type 1 revealed a dominant negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, we showed that myocytes derived from patients with long-QT syndrome type 1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype. <br /><b>Conclusions:</b><br/>We generated patient-specific pluripotent stem cells from members of a family affected by long-QT syndrome type 1 and induced them to differentiate into functional cardiac myocytes. The patient-derived cells recapitulated the electrophysiological features of the disorder. (Funded by the European Research Council and others.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Jul 2010; epub ahead of print</small></div>
Moretti A, Bellin M, Welling A, Jung CB, ... Schömig A, Laugwitz KL
N Engl J Med: 27 Jul 2010; epub ahead of print | PMID: 20660394
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<div><h4>Hospital volume and 30-day mortality for three common medical conditions.</h4><i>Ross JS, Normand SL, Wang Y, Ko DT, ... Schreiner GC, Krumholz HM</i><br />BACKGROUND: The association between hospital volume and the death rate for patients who are hospitalized for acute myocardial infarction, heart failure, or pneumonia remains unclear. It is also not known whether a volume threshold for such an association exists. <br /><b>Methods:</b><br/>We conducted cross-sectional analyses of data from Medicare administrative claims for all fee-for-service beneficiaries who were hospitalized between 2004 and 2006 in acute care hospitals in the United States for acute myocardial infarction, heart failure, or pneumonia. Using hierarchical logistic-regression models for each condition, we estimated the change in the odds of death within 30 days associated with an increase of 100 patients in the annual hospital volume. Analyses were adjusted for patients\' risk factors and hospital characteristics. Bootstrapping procedures were used to estimate 95% confidence intervals to identify the condition-specific volume thresholds above which an increased volume was not associated with reduced mortality. <br /><b>Results:</b><br/>There were 734,972 hospitalizations for acute myocardial infarction in 4128 hospitals, 1,324,287 for heart failure in 4679 hospitals, and 1,418,252 for pneumonia in 4673 hospitals. An increased hospital volume was associated with reduced 30-day mortality for all conditions (P<0.001 for all comparisons). For each condition, the association between volume and outcome was attenuated as the hospital\'s volume increased. For acute myocardial infarction, once the annual volume reached 610 patients (95% confidence interval [CI], 539 to 679), an increase in the hospital volume by 100 patients was no longer significantly associated with reduced odds of death. The volume threshold was 500 patients (95% CI, 433 to 566) for heart failure and 210 patients (95% CI, 142 to 284) for pneumonia. <br /><b>Conclusions:</b><br/>Admission to higher-volume hospitals was associated with a reduction in mortality for acute myocardial infarction, heart failure, and pneumonia, although there was a volume threshold above which an increased condition-specific hospital volume was no longer significantly associated with reduced mortality.<br /><br /><small>N Engl J Med: 25 Mar 2010; 362:1110-8</small></div>
Ross JS, Normand SL, Wang Y, Ko DT, ... Schreiner GC, Krumholz HM
N Engl J Med: 25 Mar 2010; 362:1110-8 | PMID: 20335587
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<div><h4>Upper Gastrointestinal Bleeding Due to a Peptic Ulcer.</h4><i>Laine L</i><br />Key Clinical Points Upper Gastrointestinal Bleeding Gastrointestinal bleeding is the most common cause of hospitalization due to gastrointestinal disease in the United States. Peptic ulcers, primarily due to Helicobacter pylori infection and the use of nonsteroidal antiinflammatory drugs (NSAIDs), are the most common cause of upper gastrointestinal bleeding. In patients with upper gastrointestinal bleeding, tachycardia (heart rate, ≥100 beats per minute), hypotension (systolic blood pressure, ≤100 mm Hg), age older than 60 years, and major coexisting conditions are associated with increased risks of further bleeding and death. Patients with bleeding ulcers due to H. pylori infection should receive treatment for this infection and, after eradication is confirmed, discontinue antisecretory medications. Patients with bleeding ulcers due to NSAIDs other than low-dose aspirin should discontinue NSAIDs; if NSAIDs must be resumed, a cyclooxygenase-2 (COX-2)-selective NSAID plus a proton-pump inhibitor should be used. Patients with bleeding ulcers due to low-dose aspirin taken for secondary cardiovascular prevention should resume the use of aspirin within 1 to 7 days after bleeding stops.<br /><br /><small>N Engl J Med: 14 Jun 2016; 374:2367-2376</small></div>
Laine L
N Engl J Med: 14 Jun 2016; 374:2367-2376 | PMID: 27305194
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<div><h4>Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus.</h4><i>The ACCORD Study Group</i><br />BACKGROUND: There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. <br /><b>Methods:</b><br/>A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. <br /><b>Results:</b><br/>After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). <br /><b>Conclusions:</b><br/>In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 15 Mar 2010; epub ahead of print</small></div>
The ACCORD Study Group
N Engl J Med: 15 Mar 2010; epub ahead of print | PMID: 20228401
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<div><h4>The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans.</h4><i>Quarta CC, Buxbaum JN, Shah AM, Falk RH, ... Boerwinkle E, Solomon SD</i><br /><b>Background:</b><br/>Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. Methods We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. Results After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro-brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. <br /><b>Conclusions:</b><br/>We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.).<br /><br /><small>N Engl J Med: 31 Dec 2014; 372:21-9</small></div>
Quarta CC, Buxbaum JN, Shah AM, Falk RH, ... Boerwinkle E, Solomon SD
N Engl J Med: 31 Dec 2014; 372:21-9 | PMID: 25551524
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<div><h4>Safety of Recombinant Activated Factor VII in Randomized Clinical Trials.</h4><i>Levi M, Levy JH, Andersen HF, Truloff D</i><br /><b>Background:</b><br/>The use of recombinant activated factor VII (rFVIIa) on an off-label basis to treat life-threatening bleeding has been associated with a perceived increased risk of thromboembolic complications. However, data from placebo-controlled trials are needed to properly assess the thromboembolic risk. To address this issue, we evaluated the rate of thromboembolic events in all published randomized, placebo-controlled trials of rFVIIa used on an off-label basis. Methods We analyzed data from 35 randomized clinical trials (26 studies involving patients and 9 studies involving healthy volunteers) to determine the frequency of thromboembolic events. The data were pooled with the use of random-effects models to calculate the odds ratios and 95% confidence intervals. Results Among 4468 subjects (4119 patients and 349 healthy volunteers), 498 had thromboembolic events (11.1%). Rates of arterial thromboembolic events among all 4468 subjects were higher among those who received rFVIIa than among those who received placebo (5.5% vs. 3.2%, P=0.003). Rates of venous thromboembolic events were similar among subjects who received rFVIIa and those who received placebo (5.3% vs. 5.7%). Among subjects who received rFVIIa, 2.9% had coronary arterial thromboembolic events, as compared with 1.1% of those who received placebo (P=0.002). Rates of arterial thromboembolic events were higher among subjects who received rFVIIa than among subjects who received placebo, particularly among those who were 65 years of age or older (9.0% vs. 3.8%, P=0.003); the rates were especially high among subjects 75 years of age or older (10.8% vs. 4.1%, P=0.02). <br /><b>Conclusions:</b><br/>In a large and comprehensive cohort of persons in placebo-controlled trials of rFVIIa, treatment with high doses of rFVIIa on an off-label basis significantly increased the risk of arterial but not venous thromboembolic events, especially among the elderly. (Funded by Novo Nordisk.).<br /><br /><small>N Engl J Med: 04 Nov 2010; 363:1791-800</small></div>
Levi M, Levy JH, Andersen HF, Truloff D
N Engl J Med: 04 Nov 2010; 363:1791-800 | PMID: 21047223
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<div><h4>A Randomized, Controlled Trial of Early versus Late Initiation of Dialysis.</h4><i>Cooper BA, Branley P, Bulfone L, Collins JF, ... Pollock CA, the IDEAL Study</i><br />BACKGROUND: In clinical practice, there is considerable variation in the timing of the initiation of maintenance dialysis for patients with stage V chronic kidney disease, with a worldwide trend toward early initiation. In this study, conducted at 32 centers in Australia and New Zealand, we examined whether the timing of the initiation of maintenance dialysis influenced survival among patients with chronic kidney disease. <br /><b>Methods:</b><br/>We randomly assigned patients 18 years of age or older with progressive chronic kidney disease and an estimated glomerular filtration rate (GFR) between 10.0 and 15.0 ml per minute per 1.73 m(2) of body-surface area (calculated with the use of the Cockcroft-Gault equation) to planned initiation of dialysis when the estimated GFR was 10.0 to 14.0 ml per minute (early start) or when the estimated GFR was 5.0 to 7.0 ml per minute (late start). The primary outcome was death from any cause. <br /><b>Results:</b><br/>Between July 2000 and November 2008, a total of 828 adults (mean age, 60.4 years; 542 men and 286 women; 355 with diabetes) underwent randomization, with a median time to the initiation of dialysis of 1.80 months (95% confidence interval [CI], 1.60 to 2.23) in the early-start group and 7.40 months (95% CI, 6.23 to 8.27) in the late-start group. A total of 75.9% of the patients in the late-start group initiated dialysis when the estimated GFR was above the target of 7.0 ml per minute, owing to the development of symptoms. During a median follow-up period of 3.59 years, 152 of 404 patients in the early-start group (37.6%) and 155 of 424 in the late-start group (36.6%) died (hazard ratio with early initiation, 1.04; 95% CI, 0.83 to 1.30; P=0.75). There was no significant difference between the groups in the frequency of adverse events (cardiovascular events, infections, or complications of dialysis). <br /><b>Conclusions:</b><br/>In this study, planned early initiation of dialysis in patients with stage V chronic kidney disease was not associated with an improvement in survival or clinical outcomes. (Australian New Zealand Clinical Trials Registry number, 12609000266268.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 28 Jun 2010; epub ahead of print</small></div>
Cooper BA, Branley P, Bulfone L, Collins JF, ... Pollock CA, the IDEAL Study
N Engl J Med: 28 Jun 2010; epub ahead of print | PMID: 20581422
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<div><h4>Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus.</h4><i>The ACCORD Study Group</i><br />BACKGROUND: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. <br /><b>Methods:</b><br/>We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. <br /><b>Results:</b><br/>The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction). <br /><b>Conclusions:</b><br/>The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 15 Mar 2010; epub ahead of print</small></div>
The ACCORD Study Group
N Engl J Med: 15 Mar 2010; epub ahead of print | PMID: 20228404
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<div><h4>Zika Virus Infection in Pregnant Women in Rio de Janeiro - Preliminary Report.</h4><i>Brasil P, Pereira JP, Raja Gabaglia C, Damasceno L, ... Bispo de Filippis AM, Nielsen-Saines K</i><br /><b>Background:</b><br/>Zika virus (ZIKV) has been linked to neonatal microcephaly. To characterize the spectrum of ZIKV disease in pregnancy, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in fetuses. Methods We enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse-transcriptase-polymerase-chain-reaction assays. We followed the women prospectively and collected clinical and ultrasonographic data. Results A total of 88 women were enrolled from September 2015 through February 2016; of these 88 women, 72 (82%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 5 to 38 weeks of gestation. Predominant clinical features included pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, and headache; 28% had fever (short-term and low-grade). Women who were positive for ZIKV were more likely than those who were negative for the virus to have maculopapular rash (44% vs. 12%, P=0.02), conjunctival involvement (58% vs. 13%, P=0.002), and lymphadenopathy (40% vs. 7%, P=0.02). Fetal ultrasonography was performed in 42 ZIKV-positive women (58%) and in all ZIKV-negative women. Fetal abnormalities were detected by Doppler ultrasonography in 12 of the 42 ZIKV-positive women (29%) and in none of the 16 ZIKV-negative women. Adverse findings included fetal deaths at 36 and 38 weeks of gestation (2 fetuses), in utero growth restriction with or without microcephaly (5 fetuses), ventricular calcifications or other central nervous system (CNS) lesions (7 fetuses), and abnormal amniotic fluid volume or cerebral or umbilical artery flow (7 fetuses). To date, 8 of the 42 women in whom fetal ultrasonography was performed have delivered their babies, and the ultrasonographic findings have been confirmed. <br /><b>Conclusions:</b><br/>Despite mild clinical symptoms, ZIKV infection during pregnancy appears to be associated with grave outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS injury.<br /><br /><small>N Engl J Med: 03 Mar 2016; epub ahead of print</small></div>
Brasil P, Pereira JP, Raja Gabaglia C, Damasceno L, ... Bispo de Filippis AM, Nielsen-Saines K
N Engl J Med: 03 Mar 2016; epub ahead of print | PMID: 26943629
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<div><h4>Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes.</h4><i>Tricoci P, Huang Z, Held C, Moliterno DJ, ... Mahaffey KW, the TRACER Investigators</i><br /><b>Background:</b><br/> Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. Results Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. <br /><b>Conclusions:</b><br/> In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943 .).<br /><br /><small>N Engl J Med: 14 Nov 2011; epub ahead of print</small></div>
Tricoci P, Huang Z, Held C, Moliterno DJ, ... Mahaffey KW, the TRACER Investigators
N Engl J Med: 14 Nov 2011; epub ahead of print | PMID: 22077816
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<div><h4>Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.</h4><i>Leon MB, Smith CR, Mack M, Miller DC, ... Pocock S, PARTNER Trial Investigators</i><br />BACKGROUND: Many patients with severe aortic stenosis and coexisting conditions are not candidates for surgical replacement of the aortic valve. Recently, transcatheter aortic-valve implantation (TAVI) has been suggested as a less invasive treatment for high-risk patients with aortic stenosis. <br /><b>Methods:</b><br/>We randomly assigned patients with severe aortic stenosis, whom surgeons considered not to be suitable candidates for surgery, to standard therapy (including balloon aortic valvuloplasty) or transfemoral transcatheter implantation of a balloon-expandable bovine pericardial valve. The primary end point was the rate of death from any cause. <br /><b>Results:</b><br/>A total of 358 patients with aortic stenosis who were not considered to be suitable candidates for surgery underwent randomization at 21 centers (17 in the United States). At 1 year, the rate of death from any cause (Kaplan–Meier analysis) was 30.7% with TAVI, as compared with 50.7% with standard therapy (hazard ratio with TAVI, 0.55; 95% confidence interval [CI], 0.40 to 0.74; P<0.001). The rate of the composite end point of death from any cause or repeat hospitalization was 42.5% with TAVI as compared with 71.6% with standard therapy (hazard ratio, 0.46; 95% CI, 0.35 to 0.59; P<0.001). Among survivors at 1 year, the rate of cardiac symptoms (New York Heart Association class III or IV) was lower among patients who had undergone TAVI than among those who had received standard therapy (25.2% vs. 58.0%, P<0.001). At 30 days, TAVI, as compared with standard therapy, was associated with a higher incidence of major strokes (5.0% vs. 1.1%, P=0.06) and major vascular complications (16.2% vs. 1.1%, P<0.001). In the year after TAVI, there was no deterioration in the functioning of the bioprosthetic valve, as assessed by evidence of stenosis or regurgitation on an echocardiogram. <br /><b>Conclusions:</b><br/>In patients with severe aortic stenosis who were not suitable candidates for surgery, TAVI, as compared with standard therapy, significantly reduced the rates of death from any cause, the composite end point of death from any cause or repeat hospitalization, and cardiac symptoms, despite the higher incidence of major strokes and major vascular events. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.).<br /><br /><small>N Engl J Med: 21 Oct 2010; 363:1597-607</small></div>
Leon MB, Smith CR, Mack M, Miller DC, ... Pocock S, PARTNER Trial Investigators
N Engl J Med: 21 Oct 2010; 363:1597-607 | PMID: 20961243
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<div><h4>Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events.</h4><i>The NAVIGATOR Study Group</i><br />BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. <br /><b>Methods:</b><br/>In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. <br /><b>Results:</b><br/>After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. <br /><b>Conclusions:</b><br/>Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 15 Mar 2010; epub ahead of print</small></div>
The NAVIGATOR Study Group
N Engl J Med: 15 Mar 2010; epub ahead of print | PMID: 20228402
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<div><h4>Physician cost profiling--reliability and risk of misclassification.</h4><i>Adams JL, Mehrotra A, Thomas JW, McGlynn EA</i><br />BACKGROUND: Insurance products with incentives for patients to choose physicians classified as offering lower-cost care on the basis of cost-profiling tools are increasingly common. However, no rigorous evaluation has been undertaken to determine whether these tools can accurately distinguish higher-cost physicians from lower-cost physicians. <br /><b>Methods:</b><br/>We aggregated claims data for the years 2004 and 2005 from four health plans in Massachusetts. We used commercial software to construct clinically homogeneous episodes of care (e.g., treatment of diabetes, heart attack, or urinary tract infection), assigned each episode to a physician, and created a summary profile of resource use (i.e., cost) for each physician on the basis of all assigned episodes. We estimated the reliability (signal-to-noise ratio) of each physician\'s cost-profile score on a scale of 0 to 1, with 0 indicating that all differences in physicians\' cost profiles are due to a lack of precision in the measure (noise) and 1 indicating that all differences are due to real variation in costs of services (signal). We used the reliability results to estimate the proportion of physicians in each specialty whose cost performance would be classified inaccurately in a two-tiered insurance product in which the physicians with cost profiles in the lowest quartile were labeled as "lower cost." <br /><b>Results:</b><br/>Median reliabilities ranged from 0.05 for vascular surgery to 0.79 for gastroenterology and otolaryngology. Overall, 59% of physicians had cost-profile scores with reliabilities of less than 0.70, a commonly used marker of suboptimal reliability. Using our reliability results, we estimated that 22% of physicians would be misclassified in a two-tiered system. <br /><b>Conclusions:</b><br/>Current methods for profiling physicians with respect to costs of services may produce misleading results.<br /><br /><small>N Engl J Med: 18 Mar 2010; 362:1014-21</small></div>
Adams JL, Mehrotra A, Thomas JW, McGlynn EA
N Engl J Med: 18 Mar 2010; 362:1014-21 | PMID: 20237347
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<div><h4>Abciximab and Heparin versus Bivalirudin for Non-ST-Elevation Myocardial Infarction.</h4><i>Kastrati A, Neumann FJ, Schulz S, Massberg S, ... Mehilli J, the ISAR-REACT 4 Trial Investigators</i><br /><b>Background:</b><br/> The combination of glycoprotein IIb/IIIa inhibitors and heparin has not been compared with bivalirudin in studies specifically involving patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compared the two treatments in this patient population. Methods Immediately before PCI, we randomly assigned, in a double-blind manner, 1721 patients with acute non-ST-segment elevation myocardial infarction to receive abciximab plus unfractionated heparin (861 patients) or bivalirudin (860 patients). The study tested the hypothesis that abciximab and heparin would be superior to bivalirudin with respect to the primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days. Secondary end points included the composite of death, any recurrent myocardial infarction, or urgent target-vessel revascularization (efficacy end point) and major bleeding (safety end point) within 30 days. Results The primary end point occurred in 10.9% of the patients in the abciximab group (94 patients) and in 11.0% in the bivalirudin group (95 patients) (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P=0.94). Death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the patients in the abciximab group (110 patients) and in 13.4% in the bivalirudin group (115 patients) (relative risk, 0.96; 95% CI, 0.74 to 1.25; P=0.76). Major bleeding occurred in 4.6% of the patients in the abciximab group (40 patients) as compared with 2.6% in the bivalirudin group (22 patients) (relative risk, 1.84; 95% CI, 1.10 to 3.07; P=0.02). <br /><b>Conclusions:</b><br/> Abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary end point and increased the risk of bleeding among patients with non-ST-segment elevation myocardial infarction who were undergoing PCI. (Funded by Nycomed Pharma and others; ISAR-REACT 4 ClinicalTrials.gov number, NCT00373451 .).<br /><br /><small>N Engl J Med: 14 Nov 2011; epub ahead of print</small></div>
Kastrati A, Neumann FJ, Schulz S, Massberg S, ... Mehilli J, the ISAR-REACT 4 Trial Investigators
N Engl J Med: 14 Nov 2011; epub ahead of print | PMID: 22077909
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<div><h4>A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest.</h4><i>Aufderheide TP, Nichol G, Rea TD, Brown SP, ... Sopko G, the Resuscitation Outcomes Consortium (ROC) Investigators</i><br /><b>Background:</b><br/>The impedance threshold device (ITD) is designed to enhance venous return and cardiac output during cardiopulmonary resuscitation (CPR) by increasing the degree of negative intrathoracic pressure. Previous studies have suggested that the use of an ITD during CPR may improve survival rates after cardiac arrest. Methods We compared the use of an active ITD with that of a sham ITD in patients with out-of-hospital cardiac arrest who underwent standard CPR at 10 sites in the United States and Canada. Patients, investigators, study coordinators, and all care providers were unaware of the treatment assignments. The primary outcome was survival to hospital discharge with satisfactory function (i.e., a score of ≤3 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating greater disability). Results Of 8718 patients included in the analysis, 4345 were randomly assigned to treatment with a sham ITD and 4373 to treatment with an active device. A total of 260 patients (6.0%) in the sham-ITD group and 254 patients (5.8%) in the active-ITD group met the primary outcome (risk difference adjusted for sequential monitoring, -0.1 percentage points; 95% confidence interval, -1.1 to 0.8; P=0.71). There were also no significant differences in the secondary outcomes, including rates of return of spontaneous circulation on arrival at the emergency department, survival to hospital admission, and survival to hospital discharge. <br /><b>Conclusions:</b><br/>Use of the ITD did not significantly improve survival with satisfactory function among patients with out-of-hospital cardiac arrest receiving standard CPR. (Funded by the National Heart, Lung, and Blood Institute and others; ROC PRIMED ClinicalTrials.gov number, NCT00394706 .).<br /><br /><small>N Engl J Med: 01 Sep 2011; 365:798-806</small></div>
Aufderheide TP, Nichol G, Rea TD, Brown SP, ... Sopko G, the Resuscitation Outcomes Consortium (ROC) Investigators
N Engl J Med: 01 Sep 2011; 365:798-806 | PMID: 21879897
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<div><h4>Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome.</h4><i>Alexander JH, Lopes RD, James S, Kilaru R, ... Wallentin L, the APPRAISE-2 Investigators</i><br /><b>Background:</b><br/>Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. Methods We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. Results The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary end point of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. <br /><b>Conclusions:</b><br/>The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441 .).<br /><br /><small>N Engl J Med: 25 Jul 2011; epub ahead of print</small></div>
Alexander JH, Lopes RD, James S, Kilaru R, ... Wallentin L, the APPRAISE-2 Investigators
N Engl J Med: 25 Jul 2011; epub ahead of print | PMID: 21780946
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<div><h4>Adverse Events Associated with Testosterone Administration.</h4><i>Basaria S, Coviello AD, Travison TG, Storer TW, ... Fiore LD, Bhasin S</i><br />BACKGROUND: Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. <br /><b>Methods:</b><br/>Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. <br /><b>Results:</b><br/>A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. <br /><b>Conclusions:</b><br/>In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Jul 2010; epub ahead of print</small></div>
Basaria S, Coviello AD, Travison TG, Storer TW, ... Fiore LD, Bhasin S
N Engl J Med: 01 Jul 2010; epub ahead of print | PMID: 20592293
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<div><h4>Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes.</h4><i>Wanner C, Inzucchi SE, Lachin JM, Fitchett D, ... Zinman B, EMPA-REG OUTCOME Investigators</i><br /><b>Background:</b><br/>Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial. Methods We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. Results Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population. <br /><b>Conclusions:</b><br/>In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676 .).<br /><br /><small>N Engl J Med: 13 Jun 2016; epub ahead of print</small></div>
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, ... Zinman B, EMPA-REG OUTCOME Investigators
N Engl J Med: 13 Jun 2016; epub ahead of print | PMID: 27299675
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<div><h4>Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management.</h4><i>Smith SR, Weissman NJ, Anderson CM, Sanchez M, ... Shanahan WR, the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group</i><br />BACKGROUND: Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight. <br /><b>Methods:</b><br/>In this double-blind clinical trial, we randomly assigned 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed. <br /><b>Results:</b><br/>At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar. <br /><b>Conclusions:</b><br/>In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 21 Jul 2010; 363:245-256</small></div>
Smith SR, Weissman NJ, Anderson CM, Sanchez M, ... Shanahan WR, the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) Study Group
N Engl J Med: 21 Jul 2010; 363:245-256 | PMID: 20647200
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<div><h4>Fractional Flow Reserve-Guided PCI for Stable Coronary Artery Disease.</h4><i>De Bruyne B, Fearon WF, Pijls NH, Barbato E, ... Jüni P, the FAME 2 Trial Investigators</i><br /><b>Background:</b><br/>We hypothesized that in patients with stable coronary artery disease and stenosis, percutaneous coronary intervention (PCI) performed on the basis of the fractional flow reserve (FFR) would be superior to medical therapy. Methods In 1220 patients with stable coronary artery disease, we assessed the FFR in all stenoses that were visible on angiography. Patients who had at least one stenosis with an FFR of 0.80 or less were randomly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone. Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry. The primary end point was a composite of death from any cause, nonfatal myocardial infarction, or urgent revascularization within 2 years. Results The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%; hazard ratio, 0.39; 95% confidence interval [CI], 0.26 to 0.57; P<0.001). This reduction was driven by a lower rate of urgent revascularization in the PCI group (4.0% vs. 16.3%; hazard ratio, 0.23; 95% CI, 0.14 to 0.38; P<0.001), with no significant between-group differences in the rates of death and myocardial infarction. Urgent revascularizations that were triggered by myocardial infarction or ischemic changes on electrocardiography were less frequent in the PCI group (3.4% vs. 7.0%, P=0.01). In a landmark analysis, the rate of death or myocardial infection from 8 days to 2 years was lower in the PCI group than in the medical-therapy group (4.6% vs. 8.0%, P=0.04). Among registry patients, the rate of the primary end point was 9.0% at 2 years. <br /><b>Conclusions:</b><br/>In patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome. Patients without ischemia had a favorable outcome with medical therapy alone. (Funded by St. Jude Medical; FAME 2 ClinicalTrials.gov number, NCT01132495 .).<br /><br /><small>N Engl J Med: 31 Aug 2014; epub ahead of print</small></div>
De Bruyne B, Fearon WF, Pijls NH, Barbato E, ... Jüni P, the FAME 2 Trial Investigators
N Engl J Med: 31 Aug 2014; epub ahead of print | PMID: 25176289
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<div><h4>Intensive Diabetes Therapy and Glomerular Filtration Rate in Type 1 Diabetes.</h4><i></i><br /><b>Background:</b><br/> An impaired glomerular filtration rate (GFR) leads to end-stage renal disease and increases the risks of cardiovascular disease and death. Persons with type 1 diabetes are at high risk for kidney disease, but there are no interventions that have been proved to prevent impairment of the GFR in this population. Methods In the Diabetes Control and Complications Trial (DCCT), 1441 persons with type 1 diabetes were randomly assigned to 6.5 years of intensive diabetes therapy aimed at achieving near-normal glucose concentrations or to conventional diabetes therapy aimed at preventing hyperglycemic symptoms. Subsequently, 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. Serum creatinine levels were measured annually throughout the course of the two studies. The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula. We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR, which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2) of body-surface area at two consecutive study visits. Results Over a median follow-up period of 22 years in the combined studies, impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy (risk reduction with intensive therapy, 50%; 95% confidence interval, 18 to 69; P=0.006). Among these participants, end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group. As compared with conventional therapy, intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2) (P<0.001 for both comparisons). The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates. <br /><b>Conclusions:</b><br/> The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360815 and NCT00360893 .).<br /><br /><small>N Engl J Med: 14 Nov 2011; epub ahead of print</small></div>
N Engl J Med: 14 Nov 2011; epub ahead of print | PMID: 22077236
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<div><h4>Surgical Ablation of Atrial Fibrillation during Mitral-Valve Surgery.</h4><i>Gillinov AM, Gelijns AC, Parides MK, DeRose JJ, ... Argenziano M, CTSN Investigators</i><br /><b>Background:</b><br/>Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited. Methods We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring). Results More patients in the ablation group than in the control group were free from atrial fibrillation at both 6 and 12 months (63.2% vs. 29.4%, P<0.001). There was no significant difference in the rate of freedom from atrial fibrillation between patients who underwent pulmonary-vein isolation and those who underwent the biatrial maze procedure (61.0% and 66.0%, respectively; P=0.60). One-year mortality was 6.8% in the ablation group and 8.7% in the control group (hazard ratio with ablation, 0.76; 95% confidence interval, 0.32 to 1.84; P=0.55). Ablation was associated with more implantations of a permanent pacemaker than was no ablation (21.5 vs. 8.1 per 100 patient-years, P=0.01). There were no significant between-group differences in major cardiac or cerebrovascular adverse events, overall serious adverse events, or hospital readmissions. <br /><b>Conclusions:</b><br/>The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00903370 .).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Gillinov AM, Gelijns AC, Parides MK, DeRose JJ, ... Argenziano M, CTSN Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25774765
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<div><h4>Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction.</h4><i>Montalescot G, Hof AW, Lapostolle F, Silvain J, ... Hamm CW, the ATLANTIC Investigators</i><br /><b>Background:</b><br/>The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown. Methods We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours\' duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days. Results The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used. <br /><b>Conclusions:</b><br/>Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580 .).<br /><br /><small>N Engl J Med: 31 Aug 2014; epub ahead of print</small></div>
Montalescot G, Hof AW, Lapostolle F, Silvain J, ... Hamm CW, the ATLANTIC Investigators
N Engl J Med: 31 Aug 2014; epub ahead of print | PMID: 25175921
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<div><h4>Tight Glycemic Control versus Standard Care after Pediatric Cardiac Surgery.</h4><i>Agus MS, Steil GM, Wypij D, Costello JM, ... Gaies MG, the SPECS Study Investigators</i><br /><b>Background:</b><br/>In some studies, tight glycemic control with insulin improved outcomes in adults undergoing cardiac surgery, but these benefits are unproven in critically ill children at risk for hyperinsulinemic hypoglycemia. We tested the hypothesis that tight glycemic control reduces morbidity after pediatric cardiac surgery. Methods In this two-center, prospective, randomized trial, we enrolled 980 children, 0 to 36 months of age, undergoing surgery with cardiopulmonary bypass. Patients were randomly assigned to either tight glycemic control (with the use of an insulin-dosing algorithm targeting a blood glucose level of 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) or standard care in the cardiac intensive care unit (ICU). Continuous glucose monitoring was used to guide the frequency of blood glucose measurement and to detect impending hypoglycemia. The primary outcome was the rate of health care-associated infections in the cardiac ICU. Secondary outcomes included mortality, length of stay, organ failure, and hypoglycemia. Results A total of 444 of the 490 children assigned to tight glycemic control (91%) received insulin versus 9 of 490 children assigned to standard care (2%). Although normoglycemia was achieved earlier with tight glycemic control than with standard care (6 hours vs. 16 hours, P<0.001) and was maintained for a greater proportion of the critical illness period (50% vs. 33%, P<0.001), tight glycemic control was not associated with a significantly decreased rate of health care-associated infections (8.6 vs. 9.9 per 1000 patient-days, P=0.67). Secondary outcomes did not differ significantly between groups, and tight glycemic control did not benefit high-risk subgroups. Only 3% of the patients assigned to tight glycemic control had severe hypoglycemia (blood glucose <40 mg per deciliter [2.2 mmol per liter]). <br /><b>Conclusions:</b><br/>Tight glycemic control can be achieved with a low hypoglycemia rate after cardiac surgery in children, but it does not significantly change the infection rate, mortality, length of stay, or measures of organ failure, as compared with standard care. (Funded by the National Heart, Lung, and Blood Institute and others; SPECS ClinicalTrials.gov number, NCT00443599 .).<br /><br /><small>N Engl J Med: 09 Sep 2012; epub ahead of print</small></div>
Agus MS, Steil GM, Wypij D, Costello JM, ... Gaies MG, the SPECS Study Investigators
N Engl J Med: 09 Sep 2012; epub ahead of print | PMID: 22957521
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<div><h4>Peripheral Artery Disease.</h4><i>Kullo IJ, Rooke TW</i><br />Key Clinical Points Peripheral Artery Disease Atherosclerotic peripheral artery disease affects more than 200 million persons worldwide, including at least 8.5 million persons in the United States, and is associated with high rates of cardiovascular events and death. Smoking and diabetes are the strongest risk factors. Noninvasive vascular testing provides information on the presence, severity, and location of peripheral artery disease. Exercise testing can uncover mild disease and quantify functional capacity. In the treatment of peripheral artery disease, the main goals are to reduce cardiovascular risk and improve functional capacity. Supervised exercise increases walking distance. Cilostazol can be used as an adjunct to an exercise program. Conventional angiography is typically performed when revascularization is being considered. Computed tomography or magnetic resonance angiography can also be useful in planning for revascularization. Revascularization, endovascular or surgical, is indicated for symptoms that persist despite medical management or for limb salvage in the context of critical limb ischemia.<br /><br /><small>N Engl J Med: 09 Mar 2016; 374:861-871</small></div>
Kullo IJ, Rooke TW
N Engl J Med: 09 Mar 2016; 374:861-871 | PMID: 26962905
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<div><h4>Incidence of Dementia over Three Decades in the Framingham Heart Study.</h4><i>Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S</i><br /><b>Background:</b><br/>The prevalence of dementia is expected to soar as the average life expectancy increases, but recent estimates suggest that the age-specific incidence of dementia is declining in high-income countries. Temporal trends are best derived through continuous monitoring of a population over a long period with the use of consistent diagnostic criteria. We describe temporal trends in the incidence of dementia over three decades among participants in the Framingham Heart Study. Methods Participants in the Framingham Heart Study have been under surveillance for incident dementia since 1975. In this analysis, which included 5205 persons 60 years of age or older, we used Cox proportional-hazards models adjusted for age and sex to determine the 5-year incidence of dementia during each of four epochs. We also explored the interactions between epoch and age, sex, apolipoprotein E ε4 status, and educational level, and we examined the effects of these interactions, as well as the effects of vascular risk factors and cardiovascular disease, on temporal trends. Results The 5-year age- and sex-adjusted cumulative hazard rates for dementia were 3.6 per 100 persons during the first epoch (late 1970s and early 1980s), 2.8 per 100 persons during the second epoch (late 1980s and early 1990s), 2.2 per 100 persons during the third epoch (late 1990s and early 2000s), and 2.0 per 100 persons during the fourth epoch (late 2000s and early 2010s). Relative to the incidence during the first epoch, the incidence declined by 22%, 38%, and 44% during the second, third, and fourth epochs, respectively. This risk reduction was observed only among persons who had at least a high school diploma (hazard ratio, 0.77; 95% confidence interval, 0.67 to 0.88). The prevalence of most vascular risk factors (except obesity and diabetes) and the risk of dementia associated with stroke, atrial fibrillation, or heart failure have decreased over time, but none of these trends completely explain the decrease in the incidence of dementia. <br /><b>Conclusions:</b><br/>Among participants in the Framingham Heart Study, the incidence of dementia has declined over the course of three decades. The factors contributing to this decline have not been completely identified. (Funded by the National Institutes of Health.).<br /><br /><small>N Engl J Med: 09 Feb 2016; 374:523-532</small></div>
Satizabal CL, Beiser AS, Chouraki V, Chêne G, Dufouil C, Seshadri S
N Engl J Med: 09 Feb 2016; 374:523-532 | PMID: 26863354
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<div><h4>Body-Mass Index in 2.3 Million Adolescents and Cardiovascular Death in Adulthood.</h4><i>Twig G, Yaniv G, Levine H, Leiba A, ... Haklai Z, Kark JD</i><br /><b>Background:</b><br/>In light of the worldwide increase in childhood obesity, we examined the association between body-mass index (BMI) in late adolescence and death from cardiovascular causes in adulthood. Methods We grouped data on BMI, as measured from 1967 through 2010 in 2.3 million Israeli adolescents (mean age, 17.3±0.4 years), according to age- and sex-specific percentiles from the U.S. Centers for Disease Control and Prevention. Primary outcomes were the number of deaths attributed to coronary heart disease, stroke, sudden death from an unknown cause, or a combination of all three categories (total cardiovascular causes) by mid-2011. Cox proportional-hazards models were used. Results During 42,297,007 person-years of follow-up, 2918 of 32,127 deaths (9.1%) were from cardiovascular causes, including 1497 from coronary heart disease, 528 from stroke, and 893 from sudden death. On multivariable analysis, there was a graded increase in the risk of death from cardiovascular causes and all causes that started among participants in the group that was in the 50th to 74th percentiles of BMI (i.e., within the accepted normal range). Hazard ratios in the obese group (≥95th percentile for BMI), as compared with the reference group in the 5th to 24th percentiles, were 4.9 (95% confidence interval [CI], 3.9 to 6.1) for death from coronary heart disease, 2.6 (95% CI, 1.7 to 4.1) for death from stroke, 2.1 (95% CI, 1.5 to 2.9) for sudden death, and 3.5 (95% CI, 2.9 to 4.1) for death from total cardiovascular causes, after adjustment for sex, age, birth year, sociodemographic characteristics, and height. Hazard ratios for death from cardiovascular causes in the same percentile groups increased from 2.0 (95% CI, 1.1 to 3.9) during follow-up for 0 to 10 years to 4.1 (95% CI, 3.1 to 5.4) during follow-up for 30 to 40 years; during both periods, hazard ratios were consistently high for death from coronary heart disease. Findings persisted in extensive sensitivity analyses. <br /><b>Conclusions:</b><br/>A BMI in the 50th to 74th percentiles, within the accepted normal range, during adolescence was associated with increased cardiovascular and all-cause mortality during 40 years of follow-up. Overweight and obesity were strongly associated with increased cardiovascular mortality in adulthood. (Funded by the Environment and Health Fund.).<br /><br /><small>N Engl J Med: 12 Apr 2016; epub ahead of print</small></div>
Twig G, Yaniv G, Levine H, Leiba A, ... Haklai Z, Kark JD
N Engl J Med: 12 Apr 2016; epub ahead of print | PMID: 27074389
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<div><h4>Bivalirudin Started during Emergency Transport for Primary PCI.</h4><i>Steg PG, van \'t Hof A, Hamm CW, Clemmensen P, ... Goldstein P, the EUROMAX Investigators</i><br /><b>Background:</b><br/>Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown. Methods We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding. Results Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients. <br /><b>Conclusions:</b><br/>Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis. (Funded by the Medicines Company; EUROMAX ClinicalTrials.gov number, NCT01087723 .).<br /><br /><small>N Engl J Med: 30 Oct 2013; epub ahead of print</small></div>
Steg PG, van 't Hof A, Hamm CW, Clemmensen P, ... Goldstein P, the EUROMAX Investigators
N Engl J Med: 30 Oct 2013; epub ahead of print | PMID: 24171490
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<div><h4>Rivaroxaban in Patients with a Recent Acute Coronary Syndrome.</h4><i>Mega JL, Braunwald E, Wiviott SD, Bassand JP, ... Gibson CM, the ATLAS ACS 2–TIMI 51 Investigators</i><br /><b>Background:</b><br/> Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome. Methods In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke. Results Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04). <br /><b>Conclusions:</b><br/> In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965 .).<br /><br /><small>N Engl J Med: 14 Nov 2011; epub ahead of print</small></div>
Mega JL, Braunwald E, Wiviott SD, Bassand JP, ... Gibson CM, the ATLAS ACS 2–TIMI 51 Investigators
N Engl J Med: 14 Nov 2011; epub ahead of print | PMID: 22077192
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<div><h4>Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children.</h4><i>Moler FW, Silverstein FS, Holubkov R, Slomine BS, ... Dean JM, THAPCA Trial Investigators</i><br /><b>Background:</b><br/>Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. Methods We conducted this trial of two targeted temperature interventions at 38 children\'s hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. Results A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. <br /><b>Conclusions:</b><br/>In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644 .).<br /><br /><small>N Engl J Med: 28 Apr 2015; epub ahead of print</small></div>
Moler FW, Silverstein FS, Holubkov R, Slomine BS, ... Dean JM, THAPCA Trial Investigators
N Engl J Med: 28 Apr 2015; epub ahead of print | PMID: 25913022
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<div><h4>Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure.</h4><i>Fox K, Ford I, Steg PG, Tardif JC, ... Ferrari R, the SIGNIFY Investigators</i><br /><b>Background:</b><br/>An elevated heart rate is an established marker of cardiovascular risk. Previous analyses have suggested that ivabradine, a heart-rate-reducing agent, may improve outcomes in patients with stable coronary artery disease, left ventricular dysfunction, and a heart rate of 70 beats per minute or more. Methods We conducted a randomized, double-blind, placebo-controlled trial of ivabradine, added to standard background therapy, in 19,102 patients who had both stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more (including 12,049 patients with activity-limiting angina [class ≥II on the Canadian Cardiovascular Society scale, which ranges from I to IV, with higher classes indicating greater limitations on physical activity owing to angina]). We randomly assigned patients to placebo or ivabradine, at a dose of up to 10 mg twice daily, with the dose adjusted to achieve a target heart rate of 55 to 60 beats per minute. The primary end point was a composite of death from cardiovascular causes or nonfatal myocardial infarction. Results At 3 months, the mean (±SD) heart rate of the patients was 60.7±9.0 beats per minute in the ivabradine group versus 70.6±10.1 beats per minute in the placebo group. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8% and 6.4%, respectively; hazard ratio, 1.08; 95% confidence interval, 0.96 to 1.20; P=0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction. Ivabradine was associated with an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina (P=0.02 for interaction). The incidence of bradycardia was higher with ivabradine than with placebo (18.0% vs. 2.3%, P<0.001). <br /><b>Conclusions:</b><br/>Among patients who had stable coronary artery disease without clinical heart failure, the addition of ivabradine to standard background therapy to reduce the heart rate did not improve outcomes. (Funded by Servier; SIGNIFY Current Controlled Trials number, ISRCTN61576291 .).<br /><br /><small>N Engl J Med: 31 Aug 2014; epub ahead of print</small></div>
Fox K, Ford I, Steg PG, Tardif JC, ... Ferrari R, the SIGNIFY Investigators
N Engl J Med: 31 Aug 2014; epub ahead of print | PMID: 25176136
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<div><h4>Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs.</h4><i>Sapp JL, Wells GA, Parkash R, Stevenson WG, ... Roux JF, Tang AS</i><br /><b>Background:</b><br/>Recurrent ventricular tachycardia among survivors of myocardial infarction with an implantable cardioverter-defibrillator (ICD) is frequent despite antiarrhythmic drug therapy. The most effective approach to management of this problem is uncertain. Methods We conducted a multicenter, randomized, controlled trial involving patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia despite the use of antiarrhythmic drugs. Patients were randomly assigned to receive either catheter ablation (ablation group) with continuation of baseline antiarrhythmic medications or escalated antiarrhythmic drug therapy (escalated-therapy group). In the escalated-therapy group, amiodarone was initiated if another agent had been used previously. The dose of amiodarone was increased if it had been less than 300 mg per day or mexiletine was added if the dose was already at least 300 mg per day. The primary outcome was a composite of death, three or more documented episodes of ventricular tachycardia within 24 hours (ventricular tachycardia storm), or appropriate ICD shock. Results Of the 259 patients who were enrolled, 132 were assigned to the ablation group and 127 to the escalated-therapy group. During a mean (±SD) of 27.9±17.1 months of follow-up, the primary outcome occurred in 59.1% of patients in the ablation group and 68.5% of those in the escalated-therapy group (hazard ratio in the ablation group, 0.72; 95% confidence interval, 0.53 to 0.98; P=0.04). There was no significant between-group difference in mortality. There were two cardiac perforations and three cases of major bleeding in the ablation group and two deaths from pulmonary toxic effects and one from hepatic dysfunction in the escalated-therapy group. <br /><b>Conclusions:</b><br/>In patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia despite antiarrhythmic drug therapy, there was a significantly lower rate of the composite primary outcome of death, ventricular tachycardia storm, or appropriate ICD shock among patients undergoing catheter ablation than among those receiving an escalation in antiarrhythmic drug therapy. (Funded by the Canadian Institutes of Health Research and others; VANISH ClinicalTrials.gov number, NCT00905853 .).<br /><br /><small>N Engl J Med: 04 May 2016; epub ahead of print</small></div>
Sapp JL, Wells GA, Parkash R, Stevenson WG, ... Roux JF, Tang AS
N Engl J Med: 04 May 2016; epub ahead of print | PMID: 27149033
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<div><h4>Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.</h4><i>Diamond MP, Legro RS, Coutifaris C, Alvero R, ... Zhang H, NICHD Reproductive Medicine Network</i><br /><b>Background:</b><br/>The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. Methods We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. Results After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. <br /><b>Conclusions:</b><br/>In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862 .).<br /><br /><small>N Engl J Med: 22 Sep 2015; 373:1230-1240</small></div>
Diamond MP, Legro RS, Coutifaris C, Alvero R, ... Zhang H, NICHD Reproductive Medicine Network
N Engl J Med: 22 Sep 2015; 373:1230-1240 | PMID: 26398071
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<div><h4>Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery.</h4><i>Carson JL, Terrin ML, Noveck H, Sanders DW, ... Magaziner J, the FOCUS Investigators</i><br /><b>Background:</b><br/> The hemoglobin threshold at which postoperative red-cell transfusion is warranted is controversial. We conducted a randomized trial to determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone surgery for hip fracture. Methods We enrolled 2016 patients who were 50 years of age or older, who had either a history of or risk factors for cardiovascular disease, and whose hemoglobin level was below 10 g per deciliter after hip-fracture surgery. We randomly assigned patients to a liberal transfusion strategy (a hemoglobin threshold of 10 g per deciliter) or a restrictive transfusion strategy (symptoms of anemia or at physician discretion for a hemoglobin level of <8 g per deciliter). The primary outcome was death or an inability to walk across a room without human assistance on 60-day follow-up. Results A median of 2 units of red cells were transfused in the liberal-strategy group and none in the restrictive-strategy group. The rates of the primary outcome were 35.2% in the liberal-strategy group and 34.7% in the restrictive-strategy group (odds ratio in the liberal-strategy group, 1.01; 95% confidence interval [CI], 0.84 to 1.22), for an absolute risk difference of 0.5 percentage points (95% CI, -3.7 to 4.7). The rates of in-hospital acute coronary syndrome or death were 4.3% and 5.2%, respectively (absolute risk difference, -0.9%; 99% CI, -3.3 to 1.6), and rates of death on 60-day follow-up were 7.6% and 6.6%, respectively (absolute risk difference, 1.0%; 99% CI, -1.9 to 4.0). The rates of other complications were similar in the two groups. <br /><b>Conclusions:</b><br/> A liberal transfusion strategy, as compared with a restrictive strategy, did not reduce rates of death or inability to walk independently on 60-day follow-up or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. (Funded by the National Heart, Lung, and Blood Institute; FOCUS ClinicalTrials.gov number, NCT00071032 .).<br /><br /><small>N Engl J Med: 15 Dec 2011; epub ahead of print</small></div>
Carson JL, Terrin ML, Noveck H, Sanders DW, ... Magaziner J, the FOCUS Investigators
N Engl J Med: 15 Dec 2011; epub ahead of print | PMID: 22168590
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<div><h4>Perioperative Rosuvastatin in Cardiac Surgery.</h4><i>Zheng Z, Jayaram R, Jiang L, Emberson J, ... Collins R, Casadei B</i><br /><b>Background:</b><br/>Complications after cardiac surgery are common and lead to substantial increases in morbidity and mortality. Meta-analyses of small randomized trials have suggested that perioperative statin therapy can prevent some of these complications. Methods We randomly assigned 1922 patients in sinus rhythm who were scheduled for elective cardiac surgery to receive perioperative rosuvastatin (at a dose of 20 mg daily) or placebo. The primary outcomes were postoperative atrial fibrillation within 5 days after surgery, as assessed by Holter electrocardiographic monitoring, and myocardial injury within 120 hours after surgery, as assessed by serial measurements of the cardiac troponin I concentration. Secondary outcomes included major in-hospital adverse events, duration of stay in the hospital and intensive care unit, left ventricular and renal function, and blood biomarkers. Results The concentrations of low-density lipoprotein cholesterol and C-reactive protein after surgery were lower in patients assigned to rosuvastatin than in those assigned to placebo (P<0.001). However, the rate of postoperative atrial fibrillation did not differ significantly between the rosuvastatin group and the placebo group (21.1% and 20.5%, respectively; odds ratio 1.04; 95% confidence interval [CI], 0.84 to 1.30; P=0.72), nor did the area under the troponin I-release curve (102 ng×hour per milliliter and 100 ng×hour per milliliter, respectively; between-group difference, 1%; 95% CI, -9 to 13; P=0.80). Subgroup analyses did not indicate benefit in any category of patient. Rosuvastatin therapy did not result in beneficial effects on any of the secondary outcomes but was associated with a significant absolute (±SE) excess of 5.4±1.9 percentage points in the rate of postoperative acute kidney injury (P=0.005). <br /><b>Conclusions:</b><br/>In this trial, perioperative statin therapy did not prevent postoperative atrial fibrillation or perioperative myocardial damage in patients undergoing elective cardiac surgery. Acute kidney injury was more common with rosuvastatin. (Funded by the British Heart Foundation and others; STICS ClinicalTrials.gov number, NCT01573143 .).<br /><br /><small>N Engl J Med: 03 May 2016; 374:1744-1753</small></div>
Zheng Z, Jayaram R, Jiang L, Emberson J, ... Collins R, Casadei B
N Engl J Med: 03 May 2016; 374:1744-1753 | PMID: 27144849
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<div><h4>Bedside Monitoring to Adjust Antiplatelet Therapy for Coronary Stenting.</h4><i>Collet JP, Cuisset T, Rangé G, Cayla G, ... Montalescot G, the ARCTIC Investigators</i><br /><b>Background:</b><br/>Patients\' responses to oral antiplatelet therapy are subject to variation. Bedside monitoring offers the opportunity to improve outcomes after coronary stenting by individualizing therapy. Methods We randomly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary end point was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later. Results In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (hazard ratio, 1.13; 95% confidence interval [CI], 0.98 to 1.29; P=0.10). The main secondary end point, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of those in the conventional-treatment group (hazard ratio, 1.06; 95% CI, 0.74 to 1.52; P=0.77). The rate of major bleeding events did not differ significantly between groups. <br /><b>Conclusions:</b><br/>This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring. (Funded by Allies in Cardiovascular Trials Initiatives and Organized Networks and others; ARCTIC ClinicalTrials.gov number, NCT00827411 .).<br /><br /><small>N Engl J Med: 04 Nov 2012; epub ahead of print</small></div>
Collet JP, Cuisset T, Rangé G, Cayla G, ... Montalescot G, the ARCTIC Investigators
N Engl J Med: 04 Nov 2012; epub ahead of print | PMID: 23121439
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<div><h4>Efficacy Results of a Trial of a Herpes Simplex Vaccine.</h4><i>Belshe RB, Leone PA, Bernstein DI, Wald A, ... Deal CD, the Herpevac Trial for Women</i><br /><b>Background:</b><br/> Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. Methods We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. Results The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). <br /><b>Conclusions:</b><br/> In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; ClinicalTrials.gov number, NCT00057330 .).<br /><br /><small>N Engl J Med: 05 Jan 2012; 366:34-43</small></div>
Belshe RB, Leone PA, Bernstein DI, Wald A, ... Deal CD, the Herpevac Trial for Women
N Engl J Med: 05 Jan 2012; 366:34-43 | PMID: 22216840
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<div><h4>ADHD Drugs and Serious Cardiovascular Events in Children and Young Adults.</h4><i>Cooper WO, Habel LA, Sox CM, Chan KA, ... Connell FA, Ray WA</i><br /><b>Background:</b><br/> Adverse-event reports from North America have raised concern that the use of drugs for attention deficit-hyperactivity disorder (ADHD) increases the risk of serious cardiovascular events. Methods We conducted a retrospective cohort study with automated data from four health plans (Tennessee Medicaid, Washington State Medicaid, Kaiser Permanente California, and OptumInsight Epidemiology), with 1,200,438 children and young adults between the ages of 2 and 24 years and 2,579,104 person-years of follow-up, including 373,667 person-years of current use of ADHD drugs. We identified serious cardiovascular events (sudden cardiac death, acute myocardial infarction, and stroke) from health-plan data and vital records, with end points validated by medical-record review. We estimated the relative risk of end points among current users, as compared with nonusers, with hazard ratios from Cox regression models. Results Cohort members had 81 serious cardiovascular events (3.1 per 100,000 person-years). Current users of ADHD drugs were not at increased risk for serious cardiovascular events (adjusted hazard ratio, 0.75; 95% confidence interval [CI], 0.31 to 1.85). Risk was not increased for any of the individual end points, or for current users as compared with former users (adjusted hazard ratio, 0.70; 95% CI, 0.29 to 1.72). Alternative analyses addressing several study assumptions also showed no significant association between the use of an ADHD drug and the risk of a study end point. <br /><b>Conclusions:</b><br/> This large study showed no evidence that current use of an ADHD drug was associated with an increased risk of serious cardiovascular events, although the upper limit of the 95% confidence interval indicated that a doubling of the risk could not be ruled out. However, the absolute magnitude of such an increased risk would be low. (Funded by the Agency for Healthcare Research and Quality and the Food and Drug Administration.).<br /><br /><small>N Engl J Med: 02 Nov 2011; epub ahead of print</small></div>
Cooper WO, Habel LA, Sox CM, Chan KA, ... Connell FA, Ray WA
N Engl J Med: 02 Nov 2011; epub ahead of print | PMID: 22043968
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<div><h4>Cryptogenic Stroke.</h4><i>Saver JL</i><br />Key Clinical Points Cryptogenic Stroke One quarter of patients with ischemic stroke have no probable cause found after standard workup, including echocardiography, inpatient cardiac telemetry or 24-hour Holter monitoring, magnetic resonance imaging or computed tomographic (CT) imaging of topographic features of the infarct in the brain, and magnetic resonance or CT angiographic assessment of neck and brain arteries. Additional investigation identifies a likely mechanism in more than half these patients. Most cryptogenic ischemic strokes are embolic in origin, arising from proximal arterial sources, the heart, or venous sources (with right-to-left shunts). Investigation in patients with cryptogenic stroke typically includes evaluation for atherosclerotic and nonatherosclerotic arteriopathies, cardiac sources of embolism (structural and rhythm abnormalities), and disturbances of coagulation. Patent foramen ovale is found in up to half of young adults with cryptogenic stroke but is also found in one quarter of healthy persons. Occult, low-burden, paroxysmal atrial fibrillation is increasingly recognized as a source of cryptogenic stroke, especially in older patients.<br /><br /><small>N Engl J Med: 24 May 2016; 374:2065-2074</small></div>
Saver JL
N Engl J Med: 24 May 2016; 374:2065-2074 | PMID: 27223148
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<div><h4>Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease.</h4><i>Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators</i><br /><b>Background:</b><br/>The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. Methods Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. Results We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). <br /><b>Conclusions:</b><br/>We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).<br /><br /><small>N Engl J Med: 01 Mar 2016; epub ahead of print</small></div>
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
N Engl J Med: 01 Mar 2016; epub ahead of print | PMID: 26934567
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<div><h4>Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea.</h4><i>Bah EI, Lamah MC, Fletcher T, Jacob ST, ... Pinto R, Fowler RA</i><br /><b>Background:</b><br/>In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. Methods From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. Results Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). <br /><b>Conclusions:</b><br/>Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.<br /><br /><small>N Engl J Med: 04 Nov 2014; epub ahead of print</small></div>
Bah EI, Lamah MC, Fletcher T, Jacob ST, ... Pinto R, Fowler RA
N Engl J Med: 04 Nov 2014; epub ahead of print | PMID: 25372658
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<div><h4>Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure.</h4><i>McMurray JJ, Packer M, Desai AS, Gong J, ... Zile MR, the PARADIGM-HF Investigators and Committees</i><br /><b>Background:</b><br/>We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. <br /><b>Conclusions:</b><br/>LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255 .).<br /><br /><small>N Engl J Med: 31 Aug 2014; epub ahead of print</small></div>
McMurray JJ, Packer M, Desai AS, Gong J, ... Zile MR, the PARADIGM-HF Investigators and Committees
N Engl J Med: 31 Aug 2014; epub ahead of print | PMID: 25176015
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<div><h4>The Relationship between Hospital Admission Rates and Rehospitalizations.</h4><i>Epstein AM, Jha AK, Orav EJ</i><br /><b>Background:</b><br/> Efforts to reduce hospital readmissions have focused primarily on improving transitional care. Yet variation in readmission rates may more closely reflect variation in the underlying hospitalization rates than differences in the quality of care during and after discharge. Methods We used national Medicare data to calculate, for each local hospital referral region (HRR), the 30-day, 60-day, and 90-day readmission rates among patients discharged with congestive heart failure or pneumonia. We also calculated population-based all-cause admission rates among Medicare enrollees in each HRR. We examined the variation in HRR readmission rates that was explained by overall hospitalization rates versus differences in patients\' coexisting conditions, quality of discharge planning, physician supply, and bed supply. Results HRR readmission rates ranged from 11 to 32% for congestive heart failure and from 8 to 27% for pneumonia. In univariate analyses, all-cause admission rates accounted for the highest proportion of regional variation in readmission rates for congestive heart failure (28%, 34%, and 37% at 30, 60, and 90 days, respectively); the next highest proportions were explained by case mix (11%, 15%, and 18%) and the number of cardiologists per capita (12%, 14%, and 15%). Results for pneumonia were similar, except that the number of pulmonologists per capita accounted for a lower proportion of the variation (6%, 8%, and 7%, respectively). In multivariate analyses, admission rates accounted for 16 to 24% of the variation for congestive heart failure and 11 to 20% for pneumonia; no other factor accounted for more than 6%. <br /><b>Conclusions:</b><br/> We found a substantial association between regional rates of rehospitalization and overall admission rates. Programs directed at shared savings from lower utilization of hospital services might be more successful in reducing readmissions than programs initiated to date. (Funded by the Commonwealth Fund.).<br /><br /><small>N Engl J Med: 15 Dec 2011; 365:2287-95</small></div>
Epstein AM, Jha AK, Orav EJ
N Engl J Med: 15 Dec 2011; 365:2287-95 | PMID: 22168643
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<div><h4>Outcomes 1 Year after Thrombus Aspiration for Myocardial Infarction.</h4><i>Lagerqvist B, Fröbert O, Olivecrona GK, Gudnason T, ... Ostlund O, James SK</i><br /><b>Background:</b><br/>Routine intracoronary thrombus aspiration before primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) has not been proved to reduce short-term mortality. We evaluated clinical outcomes at 1 year after thrombus aspiration. Methods We randomly assigned 7244 patients with STEMI to undergo manual thrombus aspiration followed by PCI or to undergo PCI alone, in a registry-based, randomized clinical trial. The primary end point of all-cause mortality at 30 days has been reported previously. Death from any cause at 1 year was a prespecified secondary end point of the trial. Results No patients were lost to follow-up. Death from any cause occurred in 5.3% of the patients (191 of 3621 patients) in the thrombus-aspiration group, as compared with 5.6% (202 of 3623) in the PCI-only group (hazard ratio, 0.94; 95% confidence interval [CI], 0.78 to 1.15; P=0.57). Rehospitalization for myocardial infarction at 1 year occurred in 2.7% and 2.7% of the patients, respectively (hazard ratio, 0.97; 95% CI, 0.73 to 1.28; P=0.81), and stent thrombosis in 0.7% and 0.9%, respectively (hazard ratio, 0.84; 95% CI, 0.50 to 1.40; P=0.51). The composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis occurred in 8.0% and 8.5% of the patients, respectively (hazard ratio, 0.94; 95% CI, 0.80 to 1.11; P=0.48). The results were consistent across all the major subgroups, including grade of thrombus burden and coronary flow before PCI. <br /><b>Conclusions:</b><br/>Routine thrombus aspiration before PCI in patients with STEMI did not reduce the rate of death from any cause or the composite of death from any cause, rehospitalization for myocardial infarction, or stent thrombosis at 1 year. (Funded by the Swedish Research Council and others; TASTE ClinicalTrials.gov number, NCT01093404 .).<br /><br /><small>N Engl J Med: 31 Aug 2014; epub ahead of print</small></div>
Lagerqvist B, Fröbert O, Olivecrona GK, Gudnason T, ... Ostlund O, James SK
N Engl J Med: 31 Aug 2014; epub ahead of print | PMID: 25176395
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<div><h4>Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease.</h4><i>Dewey FE, Gusarova V, O\'Dushlaine C, Gottesman O, ... Gromada J, Shuldiner AR</i><br /><b>Background:</b><br/>Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides. Methods We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys. Results We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels. <br /><b>Conclusions:</b><br/>Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).<br /><br /><small>N Engl J Med: 01 Mar 2016; epub ahead of print</small></div>
Dewey FE, Gusarova V, O'Dushlaine C, Gottesman O, ... Gromada J, Shuldiner AR
N Engl J Med: 01 Mar 2016; epub ahead of print | PMID: 26933753
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<div><h4>Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease.</h4><i>Douglas PS, Hoffmann U, Patel MR, Mark DB, ... Lee KL, PROMISE Investigators</i><br /><b>Background:</b><br/>Many patients have symptoms suggestive of coronary artery disease (CAD) and are often evaluated with the use of diagnostic testing, although there are limited data from randomized trials to guide care. Methods We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. Results The mean age of the patients was 60.8±8.3 years, 52.7% were women, and 87.7% had chest pain or dyspnea on exertion. The mean pretest likelihood of obstructive CAD was 53.3±21.4%. Over a median follow-up period of 25 months, a primary end-point event occurred in 164 of 4996 patients in the CTA group (3.3%) and in 151 of 5007 (3.0%) in the functional-testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; P=0.75). CTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%, P=0.02), although more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%). The median cumulative radiation exposure per patient was lower in the CTA group than in the functional-testing group (10.0 mSv vs. 11.3 mSv), but 32.6% of the patients in the functional-testing group had no exposure, so the overall exposure was higher in the CTA group (mean, 12.0 mSv vs. 10.1 mSv; P<0.001). <br /><b>Conclusions:</b><br/>In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550 .).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Douglas PS, Hoffmann U, Patel MR, Mark DB, ... Lee KL, PROMISE Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25773919
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<div><h4>A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia.</h4><i>Blom DJ, Hala T, Bolognese M, Lillestol MJ, ... Stein EA, the DESCARTES Investigators</i><br /><b>Background:</b><br/>Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab. Methods We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52. Results Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain. <br /><b>Conclusions:</b><br/>At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879 .).<br /><br /><small>N Engl J Med: 30 Mar 2014; epub ahead of print</small></div>
Blom DJ, Hala T, Bolognese M, Lillestol MJ, ... Stein EA, the DESCARTES Investigators
N Engl J Med: 30 Mar 2014; epub ahead of print | PMID: 24678979
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<div><h4>Norovirus Vaccine against Experimental Human Norwalk Virus Illness.</h4><i>Atmar RL, Bernstein DI, Harro CD, Al-Ibrahim MS, ... Richardson C, Mendelman PM</i><br /><b>Background:</b><br/> Noroviruses cause epidemic and sporadic acute gastroenteritis. No vaccine is available to prevent norovirus illness or infection. Methods We conducted a randomized, double-blind, placebo-controlled, multicenter trial to assess the safety, immunogenicity, and efficacy of an investigational, intranasally delivered norovirus viruslike particle (VLP) vaccine (with chitosan and monophosphoryl lipid A as adjuvants) to prevent acute viral gastroenteritis after challenge with a homologous viral strain, Norwalk virus (genotype GI.1). Healthy adults 18 to 50 years of age received two doses of either vaccine or placebo and were subsequently inoculated with Norwalk virus and monitored for infection and gastroenteritis symptoms. Results Ninety-eight persons were enrolled and randomly assigned to receive vaccine (50 participants) or placebo (48 participants), and 90 received both doses (47 participants in the vaccine group and 43 in the placebo group). The most commonly reported symptoms after vaccination were nasal stuffiness, nasal discharge, and sneezing. Adverse events occurred with similar frequency among vaccine and placebo recipients. A Norwalk virus-specific IgA seroresponse (defined as an increase by a factor of 4 in serum antibody levels) was detected in 70% of vaccine recipients. Seventy-seven of 84 participants inoculated with Norwalk virus were included in the per-protocol analysis. Vaccination significantly reduced the frequencies of Norwalk virus gastroenteritis (occurring in 69% of placebo recipients vs. 37% of vaccine recipients, P=0.006) and Norwalk virus infection (82% of placebo recipients vs. 61% of vaccine recipients, P=0.05). <br /><b>Conclusions:</b><br/> This norovirus VLP vaccine provides protection against illness and infection after challenge with a homologous virus. (Funded by LigoCyte Pharmaceuticals and the National Institutes of Health; ClinicalTrials.gov number, NCT00973284 .).<br /><br /><small>N Engl J Med: 13 Dec 2011; 365:2178-2187</small></div>
Atmar RL, Bernstein DI, Harro CD, Al-Ibrahim MS, ... Richardson C, Mendelman PM
N Engl J Med: 13 Dec 2011; 365:2178-2187 | PMID: 22150036
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<div><h4>Genetically Determined Height and Coronary Artery Disease.</h4><i>Nelson CP, Hamby SE, Saleheen D, Hopewell JC, ... Samani NJ, CARDIoGRAM+C4D Consortium</i><br /><b>Background:</b><br/>The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. Methods We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. Results We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. <br /><b>Conclusions:</b><br/>There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).<br /><br /><small>N Engl J Med: 07 Apr 2015; epub ahead of print</small></div>
Nelson CP, Hamby SE, Saleheen D, Hopewell JC, ... Samani NJ, CARDIoGRAM+C4D Consortium
N Engl J Med: 07 Apr 2015; epub ahead of print | PMID: 25853659
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<div><h4>Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease.</h4><i>Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A</i><br /><b>Background:</b><br/>High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown. Methods Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants. Results Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval [CI], 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04). <br /><b>Conclusions:</b><br/>Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.).<br /><br /><small>N Engl J Med: 17 Jun 2014; epub ahead of print</small></div>
Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A
N Engl J Med: 17 Jun 2014; epub ahead of print | PMID: 24941082
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<div><h4>Strategies for Multivessel Revascularization in Patients with Diabetes.</h4><i>Farkouh ME, Domanski M, Sleeper LA, Siami FS, ... Fuster V, the FREEDOM Trial Investigators</i><br /><b>Background:</b><br/>In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. Methods In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. Results From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients\' mean age was 63.1±9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). <br /><b>Conclusions:</b><br/>For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450 .).<br /><br /><small>N Engl J Med: 04 Nov 2012; epub ahead of print</small></div>
Farkouh ME, Domanski M, Sleeper LA, Siami FS, ... Fuster V, the FREEDOM Trial Investigators
N Engl J Med: 04 Nov 2012; epub ahead of print | PMID: 23121323
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<div><h4>Effects of red-cell storage duration on patients undergoing cardiac surgery.</h4><i>Steiner ME, Ness PM, Assmann SF, Triulzi DJ, ... Hod EA, Stowell CP</i><br /><b>Background:</b><br/>Some observational studies have reported that transfusion of red-cell units that have been stored for more than 2 to 3 weeks is associated with serious, even fatal, adverse events. Patients undergoingcardiac surgery may be especially vulnerable to the adverse effects of transfusion. Methods We conducted a randomized trial at multiple sites from 2010 to 2014. Participants 12 years of age or older who were undergoing complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions. The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge. Results The median storage time of red-cell units provided to the 1098 participants who received red-cell transfusion was 7 days in the shorter-term storage group and 28 days in the longer-term storage group. The mean change in MODS was an increase of 8.5 and 8.7 points, respectively (95% confidence interval for the difference, -0.6 to 0.3; P=0.44). The 7-day mortality was 2.8% in the shorter-term storage group and 2.0% in the longer-term storage group (P=0.43); 28-day mortality was 4.4% and 5.3%, respectively (P=0.57). Adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group. <br /><b>Conclusions:</b><br/>The duration of red-cell storage was not associated with significant differences in the change in MODS. We did not find that the transfusion of red cells stored for 10 days or less was superior to the transfusion of red cells stored for 21 days or more among patients 12 years of age or older who were undergoing complex cardiac surgery. (Funded by the National Heart, Lung, and Blood Institute; RECESS ClinicalTrials.gov number, NCT00991341 .).<br /><br /><small>N Engl J Med: 03 Apr 2015; 372:1419-29</small></div>
Steiner ME, Ness PM, Assmann SF, Triulzi DJ, ... Hod EA, Stowell CP
N Engl J Med: 03 Apr 2015; 372:1419-29 | PMID: 25839844
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<div><h4>Demographic and Epidemiologic Drivers of Global Cardiovascular Mortality.</h4><i>Roth GA, Forouzanfar MH, Moran AE, Barber R, ... Mensah GA, Murray CJ</i><br /><b>Background:</b><br/>Global deaths from cardiovascular disease are increasing as a result of population growth, the aging of populations, and epidemiologic changes in disease. Disentangling the effects of these three drivers on trends in mortality is important for planning the future of the health care system and benchmarking progress toward the reduction of cardiovascular disease. Methods We used mortality data from the Global Burden of Disease Study 2013, which includes data on 188 countries grouped into 21 world regions. We developed three counterfactual scenarios to represent the principal drivers of change in cardiovascular deaths (population growth alone, population growth and aging, and epidemiologic changes in disease) from 1990 to 2013. Secular trends and correlations with changes in national income were examined. Results Global deaths from cardiovascular disease increased by 41% between 1990 and 2013 despite a 39% decrease in age-specific death rates; this increase was driven by a 55% increase in mortality due to the aging of populations and a 25% increase due to population growth. The relative contributions of these drivers varied by region; only in Central Europe and Western Europe did the annual number of deaths from cardiovascular disease actually decline. Change in gross domestic product per capita was correlated with change in age-specific death rates only among upper-middle income countries, and this correlation was weak; there was no significant correlation elsewhere. <br /><b>Conclusions:</b><br/>The aging and growth of the population resulted in an increase in global cardiovascular deaths between 1990 and 2013, despite a decrease in age-specific death rates in most regions. Only Central and Western Europe had gains in cardiovascular health that were sufficient to offset these demographic forces. (Funded by the Bill and Melinda Gates Foundation and others.).<br /><br /><small>N Engl J Med: 31 Mar 2015; 372:1333-1341</small></div>
Roth GA, Forouzanfar MH, Moran AE, Barber R, ... Mensah GA, Murray CJ
N Engl J Med: 31 Mar 2015; 372:1333-1341 | PMID: 25830423
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<div><h4>Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes.</h4><i>Zoungas S, Chalmers J, Neal B, Billot L, ... Woodward M, the ADVANCE-ON Collaborative Group</i><br /><b>Background:</b><br/>In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up. Methods We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events. Results The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively. <br /><b>Conclusions:</b><br/>The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286 .).<br /><br /><small>N Engl J Med: 18 Sep 2014; epub ahead of print</small></div>
Zoungas S, Chalmers J, Neal B, Billot L, ... Woodward M, the ADVANCE-ON Collaborative Group
N Engl J Med: 18 Sep 2014; epub ahead of print | PMID: 25234206
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<div><h4>Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis.</h4><i>Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, ... Dworkin LD, the CORAL Investigators</i><br /><b>Background:</b><br/>Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain. Methods We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy). Results Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95% CI, -4.4 to -0.2; P=0.03). <br /><b>Conclusions:</b><br/>Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731 .).<br /><br /><small>N Engl J Med: 18 Nov 2013; epub ahead of print</small></div>
Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, ... Dworkin LD, the CORAL Investigators
N Engl J Med: 18 Nov 2013; epub ahead of print | PMID: 24245566
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<div><h4>Clinical diagnosis by whole-genome sequencing of a prenatal sample.</h4><i>Talkowski ME, Ordulu Z, Pillalamarri V, Benson CB, ... Gusella JF, Morton CC</i><br />Conventional cytogenetic testing offers low-resolution detection of balanced karyotypic abnormalities but cannot provide the precise, gene-level knowledge required to predict outcomes. The use of high-resolution whole-genome deep sequencing is currently impractical for the purpose of routine clinical care. We show here that whole-genome "jumping libraries" can offer an immediately applicable, nucleotide-level complement to conventional genetic diagnostics within a time frame that allows for clinical action. We performed large-insert sequencing of DNA extracted from amniotic-fluid cells with a balanced de novo translocation. The amniotic-fluid sample was from a patient in the third trimester of pregnancy who underwent amniocentesis because of severe polyhydramnios after multiple fetal anomalies had been detected on ultrasonography. Using a 13-day sequence and analysis pipeline, we discovered direct disruption of CHD7, a causal locus in the CHARGE syndrome (coloboma of the eye, heart anomaly, atresia of the choanae, retardation, and genital and ear anomalies). Clinical findings at birth were consistent with the CHARGE syndrome, a diagnosis that could not have been reliably inferred from the cytogenetic breakpoint. This case study illustrates the potential power of customized whole-genome jumping libraries when used to augment prenatal karyotyping.<br /><br /><small>N Engl J Med: 10 Dec 2012; 367:2226-32</small></div>
Talkowski ME, Ordulu Z, Pillalamarri V, Benson CB, ... Gusella JF, Morton CC
N Engl J Med: 10 Dec 2012; 367:2226-32 | PMID: 23215558
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<div><h4>Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events.</h4><i>Robinson JG, Farnier M, Krempf M, Bergeron J, ... Kastelein JJ, ODYSSEY LONG TERM Investigators</i><br /><b>Background:</b><br/>Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. Methods We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Results At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). <br /><b>Conclusions:</b><br/>Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831 .).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Robinson JG, Farnier M, Krempf M, Bergeron J, ... Kastelein JJ, ODYSSEY LONG TERM Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25773378
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<div><h4>Unexpected Abrupt Increase in Left Ventricular Assist Device Thrombosis.</h4><i>Starling RC, Moazami N, Silvestry SC, Ewald G, ... Lytle BW, Smedira NG</i><br /><b>Background:</b><br/>We observed an apparent increase in the rate of device thrombosis among patients who received the HeartMate II left ventricular assist device, as compared with preapproval clinical-trial results and initial experience. We investigated the occurrence of pump thrombosis and elevated lactate dehydrogenase (LDH) levels, LDH levels presaging thrombosis (and associated hemolysis), and outcomes of different management strategies in a multi-institutional study. Methods We obtained data from 837 patients at three institutions, where 895 devices were implanted from 2004 through mid-2013; the mean (±SD) age of the patients was 55±14 years. The primary end point was confirmed pump thrombosis. Secondary end points were confirmed and suspected thrombosis, longitudinal LDH levels, and outcomes after pump thrombosis. Results A total of 72 pump thromboses were confirmed in 66 patients; an additional 36 thromboses in unique devices were suspected. Starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% (95% confidence interval [CI], 1.5 to 3.4) to 8.4% (95% CI, 5.0 to 13.9) by January 1, 2013. Before March 1, 2011, the median time from implantation to thrombosis was 18.6 months (95% CI, 0.5 to 52.7), and from March 2011 onward, it was 2.7 months (95% CI, 0.0 to 18.6). The occurrence of elevated LDH levels within 3 months after implantation mirrored that of thrombosis. Thrombosis was presaged by LDH levels that more than doubled, from 540 IU per liter to 1490 IU per liter, within the weeks before diagnosis. Thrombosis was managed by heart transplantation in 11 patients (1 patient died 31 days after transplantation) and by pump replacement in 21, with mortality equivalent to that among patients without thrombosis; among 40 thromboses in 40 patients who did not undergo transplantation or pump replacement, actuarial mortality was 48.2% (95% CI, 31.6 to 65.2) in the ensuing 6 months after pump thrombosis. <br /><b>Conclusions:</b><br/>The rate of pump thrombosis related to the use of the HeartMate II has been increasing at our centers and is associated with substantial morbidity and mortality.<br /><br /><small>N Engl J Med: 27 Nov 2013; epub ahead of print</small></div>
Starling RC, Moazami N, Silvestry SC, Ewald G, ... Lytle BW, Smedira NG
N Engl J Med: 27 Nov 2013; epub ahead of print | PMID: 24283197
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<div><h4>Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex.</h4><i>Ruschitzka F, Abraham WT, Singh JP, Bax JJ, ... Holzmeister J, the EchoCRT Study Group</i><br /><b>Background:</b><br/>Cardiac-resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure with a wide QRS complex. Mechanical dyssynchrony also occurs in patients with a narrow QRS complex, which suggests the potential usefulness of CRT in such patients. Methods We conducted a randomized trial involving 115 centers to evaluate the effect of CRT in patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35% or less, a QRS duration of less than 130 msec, and echocardiographic evidence of left ventricular dyssynchrony. All patients underwent device implantation and were randomly assigned to have CRT capability turned on or off. The primary efficacy outcome was the composite of death from any cause or first hospitalization for worsening heart failure. Results On March 13, 2013, the study was stopped for futility on the recommendation of the data and safety monitoring board. At study closure, the 809 patients who had undergone randomization had been followed for a mean of 19.4 months. The primary outcome occurred in 116 of 404 patients in the CRT group, as compared with 102 of 405 in the control group (28.7% vs. 25.2%; hazard ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.57; P=0.15). There were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; hazard ratio, 1.81; 95% CI, 1.11 to 2.93; P=0.02). <br /><b>Conclusions:</b><br/>In patients with systolic heart failure and a QRS duration of less than 130 msec, CRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality. (Funded by Biotronik and GE Healthcare; EchoCRT ClinicalTrials.gov number, NCT00683696 .).<br /><br /><small>N Engl J Med: 02 Sep 2013; epub ahead of print</small></div>
Ruschitzka F, Abraham WT, Singh JP, Bax JJ, ... Holzmeister J, the EchoCRT Study Group
N Engl J Med: 02 Sep 2013; epub ahead of print | PMID: 23998714
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<div><h4>Trends in Survival after In-Hospital Cardiac Arrest.</h4><i>Girotra S, Nallamothu BK, Spertus JA, Li Y, ... Chan PS, the American Heart Association Get with the Guidelines–Resuscitation Investigators</i><br /><b>Background:</b><br/>Despite advances in resuscitation care in recent years, it is not clear whether survival and neurologic function after in-hospital cardiac arrest have improved over time. Methods We identified all adults who had an in-hospital cardiac arrest at 374 hospitals in the Get with the Guidelines-Resuscitation registry between 2000 and 2009. Using multivariable regression, we examined temporal trends in risk-adjusted rates of survival to discharge. Additional analyses explored whether trends were due to improved survival during acute resuscitation or postresuscitation care and whether they occurred at the expense of greater neurologic disability in survivors. Results Among 84,625 hospitalized patients with cardiac arrest, 79.3% had an initial rhythm of asystole or pulseless electrical activity, and 20.7% had ventricular fibrillation or pulseless ventricular tachycardia. The proportion of cardiac arrests due to asystole or pulseless electrical activity increased over time (P<0.001 for trend). Risk-adjusted rates of survival to discharge increased from 13.7% in 2000 to 22.3% in 2009 (adjusted rate ratio per year, 1.04; 95% confidence interval [CI], 1.03 to 1.06; P<0.001 for trend). Survival improvement was similar in the two rhythm groups and was due to improvement in both acute resuscitation survival and postresuscitation survival. Rates of clinically significant neurologic disability among survivors decreased over time, with a risk-adjusted rate of 32.9% in 2000 and 28.1% in 2009 (adjusted rate ratio per year, 0.98; 95% CI, 0.97 to 1.00; P=0.02 for trend). <br /><b>Conclusions:</b><br/>Both survival and neurologic outcomes after in-hospital cardiac arrest have improved during the past decade at hospitals participating in a large national quality-improvement registry. (Funded by the American Heart Association.).<br /><br /><small>N Engl J Med: 14 Nov 2012; 367:1912-1920</small></div>
Girotra S, Nallamothu BK, Spertus JA, Li Y, ... Chan PS, the American Heart Association Get with the Guidelines–Resuscitation Investigators
N Engl J Med: 14 Nov 2012; 367:1912-1920 | PMID: 23150959
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<div><h4>A Prospective Study of Sudden Cardiac Death among Children and Young Adults.</h4><i>Bagnall RD, Weintraub RG, Ingles J, Duflou J, ... Skinner JR, Semsarian C</i><br /><b>Background:</b><br/>Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. Methods We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. Results A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. <br /><b>Conclusions:</b><br/>The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).<br /><br /><small>N Engl J Med: 21 Jun 2016; 374:2441-2452</small></div>
Bagnall RD, Weintraub RG, Ingles J, Duflou J, ... Skinner JR, Semsarian C
N Engl J Med: 21 Jun 2016; 374:2441-2452 | PMID: 27332903
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<div><h4>Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk.</h4><i>Urban P, Meredith IT, Abizaid A, Pocock SJ, ... Morice MC, LEADERS FREE Investigators</i><br /><b>Background:</b><br/>Patients at high risk for bleeding who undergo percutaneous coronary intervention (PCI) often receive bare-metal stents followed by 1 month of dual antiplatelet therapy. We studied a polymer-free and carrier-free drug-coated stent that transfers umirolimus (also known as biolimus A9), a highly lipophilic sirolimus analogue, into the vessel wall over a period of 1 month. Methods In a randomized, double-blind trial, we compared the drug-coated stent with a very similar bare-metal stent in patients with a high risk of bleeding who underwent PCI. All patients received 1 month of dual antiplatelet therapy. The primary safety end point, tested for both noninferiority and superiority, was a composite of cardiac death, myocardial infarction, or stent thrombosis. The primary efficacy end point was clinically driven target-lesion revascularization. Results We enrolled 2466 patients. At 390 days, the primary safety end point had occurred in 112 patients (9.4%) in the drug-coated-stent group and in 154 patients (12.9%) in the bare-metal-stent group (risk difference, -3.6 percentage points; 95% confidence interval [CI], -6.1 to -1.0; hazard ratio, 0.71; 95% CI, 0.56 to 0.91; P<0.001 for noninferiority and P=0.005 for superiority). During the same time period, clinically driven target-lesion revascularization was needed in 59 patients (5.1%) in the drug-coated-stent group and in 113 patients (9.8%) in the bare-metal-stent group (risk difference, -4.8 percentage points; 95% CI, -6.9 to -2.6; hazard ratio, 0.50; 95% CI, 0.37 to 0.69; P<0.001). <br /><b>Conclusions:</b><br/>Among patients at high risk for bleeding who underwent PCI, a polymer-free umirolimus-coated stent was superior to a bare-metal stent with respect to the primary safety and efficacy end points when used with a 1-month course of dual antiplatelet therapy. (Funded by Biosensors Europe; LEADERS FREE ClinicalTrials.gov number, NCT01623180 .).<br /><br /><small>N Engl J Med: 13 Oct 2015; epub ahead of print</small></div>
Urban P, Meredith IT, Abizaid A, Pocock SJ, ... Morice MC, LEADERS FREE Investigators
N Engl J Med: 13 Oct 2015; epub ahead of print | PMID: 26466021
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<div><h4>Edoxaban versus Warfarin in Patients with Atrial Fibrillation.</h4><i>Giugliano RP, Ruff CT, Braunwald E, Murphy SA, ... Antman EM, the ENGAGE AF-TIMI 48 Investigators</i><br /><b>Background:</b><br/>Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. Methods We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. Results The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). <br /><b>Conclusions:</b><br/>Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391 .).<br /><br /><small>N Engl J Med: 19 Nov 2013; epub ahead of print</small></div>
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, ... Antman EM, the ENGAGE AF-TIMI 48 Investigators
N Engl J Med: 19 Nov 2013; epub ahead of print | PMID: 24251359
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<div><h4>Cardiovascular Effects of Intensive Lifestyle Intervention in Type 2 Diabetes.</h4><i>The Look AHEAD Research Group</i><br /><b>Background:</b><br/>Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients. Methods In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years. Results The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P=0.51). <br /><b>Conclusions:</b><br/>An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953 .).<br /><br /><small>N Engl J Med: 24 Jun 2013; epub ahead of print</small></div>
The Look AHEAD Research Group
N Engl J Med: 24 Jun 2013; epub ahead of print | PMID: 23796131
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<div><h4>Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome.</h4><i>Bart BA, Goldsmith SR, Lee KL, Givertz MM, ... Braunwald E, the Heart Failure Clinical Research Network</i><br /><b>Background:</b><br/>Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. Methods We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. Results Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). <br /><b>Conclusions:</b><br/>In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491 .).<br /><br /><small>N Engl J Med: 06 Nov 2012; epub ahead of print</small></div>
Bart BA, Goldsmith SR, Lee KL, Givertz MM, ... Braunwald E, the Heart Failure Clinical Research Network
N Engl J Med: 06 Nov 2012; epub ahead of print | PMID: 23131078
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<div><h4>Everolimus-Eluting Bioresorbable Scaffolds for Coronary Artery Disease.</h4><i>Ellis SG, Kereiakes DJ, Metzger DC, Caputo RP, ... Stone GW, ABSORB III Investigators</i><br /><b>Background:</b><br/>In patients with coronary artery disease who receive metallic drug-eluting coronary stents, adverse events such as late target-lesion failure may be related in part to the persistent presence of the metallic stent frame in the coronary-vessel wall. Bioresorbable vascular scaffolds have been developed to attempt to improve long-term outcomes. Methods In this large, multicenter, randomized trial, 2008 patients with stable or unstable angina were randomly assigned in a 2:1 ratio to receive an everolimus-eluting bioresorbable vascular (Absorb) scaffold (1322 patients) or an everolimus-eluting cobalt-chromium (Xience) stent (686 patients). The primary end point, which was tested for both noninferiority (margin, 4.5 percentage points for the risk difference) and superiority, was target-lesion failure (cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization) at 1 year. Results Target-lesion failure at 1 year occurred in 7.8% of patients in the Absorb group and in 6.1% of patients in the Xience group (difference, 1.7 percentage points; 95% confidence interval, -0.5 to 3.9; P=0.007 for noninferiority and P=0.16 for superiority). There was no significant difference between the Absorb group and the Xience group in rates of cardiac death (0.6% and 0.1%, respectively; P=0.29), target-vessel myocardial infarction (6.0% and 4.6%, respectively; P=0.18), or ischemia-driven target-lesion revascularization (3.0% and 2.5%, respectively; P=0.50). Device thrombosis within 1 year occurred in 1.5% of patients in the Absorb group and in 0.7% of patients in the Xience group (P=0.13). <br /><b>Conclusions:</b><br/>In this large-scale, randomized trial, treatment of noncomplex obstructive coronary artery disease with an everolimus-eluting bioresorbable vascular scaffold, as compared with an everolimus-eluting cobalt-chromium stent, was within the prespecified margin for noninferiority with respect to target-lesion failure at 1 year. (Funded by Abbott Vascular; ABSORB III ClinicalTrials.gov number, NCT01751906 .).<br /><br /><small>N Engl J Med: 11 Oct 2015; epub ahead of print</small></div>
Ellis SG, Kereiakes DJ, Metzger DC, Caputo RP, ... Stone GW, ABSORB III Investigators
N Engl J Med: 11 Oct 2015; epub ahead of print | PMID: 26457558
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<div><h4>Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure.</h4><i>Goldenberg I, Kutyifa V, Klein HU, Cannom DS, ... Zareba W, Moss AJ</i><br /><b>Background:</b><br/>The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone. Methods We evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis. Results At 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval [CI], 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundle-branch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P=0.04; P<0.001 for interaction of treatment with QRS morphologic findings). <br /><b>Conclusions:</b><br/>Our findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271 , NCT01294449 , and NCT02060110 .).<br /><br /><small>N Engl J Med: 30 Mar 2014; epub ahead of print</small></div>
Goldenberg I, Kutyifa V, Klein HU, Cannom DS, ... Zareba W, Moss AJ
N Engl J Med: 30 Mar 2014; epub ahead of print | PMID: 24678999
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<div><h4>Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes.</h4><i>Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, ... Pfeffer MA, the ALTITUDE Investigators</i><br /><b>Background:</b><br/>This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. Methods In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. Results The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). <br /><b>Conclusions:</b><br/>The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757 .).<br /><br /><small>N Engl J Med: 04 Nov 2012; epub ahead of print</small></div>
Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, ... Pfeffer MA, the ALTITUDE Investigators
N Engl J Med: 04 Nov 2012; epub ahead of print | PMID: 23121378
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<div><h4>Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.</h4><i>Zinman B, Wanner C, Lachin JM, Fitchett D, ... Inzucchi SE, EMPA-REG OUTCOME Investigators</i><br /><b>Background:</b><br/>The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. Methods We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. Results A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. <br /><b>Conclusions:</b><br/>Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676 .).<br /><br /><small>N Engl J Med: 16 Sep 2015; epub ahead of print</small></div>
Zinman B, Wanner C, Lachin JM, Fitchett D, ... Inzucchi SE, EMPA-REG OUTCOME Investigators
N Engl J Med: 16 Sep 2015; epub ahead of print | PMID: 26378978
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<div><h4>Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis.</h4><i>The EVOLVE Trial Investigators</i><br /><b>Background:</b><br/>Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients. Methods In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle. Results The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet. <br /><b>Conclusions:</b><br/>In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839 .).<br /><br /><small>N Engl J Med: 04 Nov 2012; epub ahead of print</small></div>
The EVOLVE Trial Investigators
N Engl J Med: 04 Nov 2012; epub ahead of print | PMID: 23121374
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<div><h4>Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism.</h4><i>Brighton TA, Eikelboom JW, Mann K, Mister R, ... Simes J, the ASPIRE Investigators</i><br /><b>Background:</b><br/>Patients who have had a first episode of unprovoked venous thromboembolism have a high risk of recurrence after anticoagulants are discontinued. Aspirin may be effective in preventing a recurrence of venous thromboembolism. Methods We randomly assigned 822 patients who had completed initial anticoagulant therapy after a first episode of unprovoked venous thromboembolism to receive aspirin, at a dose of 100 mg daily, or placebo for up to 4 years. The primary outcome was a recurrence of venous thromboembolism. Results During a median follow-up period of 37.2 months, venous thromboembolism recurred in 73 of 411 patients assigned to placebo and in 57 of 411 assigned to aspirin (a rate of 6.5% per year vs. 4.8% per year; hazard ratio with aspirin, 0.74; 95% confidence interval [CI], 0.52 to 1.05; P=0.09). Aspirin reduced the rate of the two prespecified secondary composite outcomes: the rate of venous thromboembolism, myocardial infarction, stroke, or cardiovascular death was reduced by 34% (a rate of 8.0% per year with placebo vs. 5.2% per year with aspirin; hazard ratio with aspirin, 0.66; 95% CI, 0.48 to 0.92; P=0.01), and the rate of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause was reduced by 33% (hazard ratio, 0.67; 95% CI, 0.49 to 0.91; P=0.01). There was no significant between-group difference in the rates of major or clinically relevant nonmajor bleeding episodes (rate of 0.6% per year with placebo vs. 1.1% per year with aspirin, P=0.22) or serious adverse events. <br /><b>Conclusions:</b><br/>In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism. (Funded by National Health and Medical Research Council [Australia] and others; Australian New Zealand Clinical Trials Registry number, ACTRN12605000004662 .).<br /><br /><small>N Engl J Med: 04 Nov 2012; epub ahead of print</small></div>
Brighton TA, Eikelboom JW, Mann K, Mister R, ... Simes J, the ASPIRE Investigators
N Engl J Med: 04 Nov 2012; epub ahead of print | PMID: 23121403
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<div><h4>Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization.</h4><i>Roe MT, Armstrong PW, Fox KA, White HD, ... Ohman EM, the TRILOGY ACS Investigators</i><br /><b>Background:</b><br/>The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. Methods In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. Results At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. <br /><b>Conclusions:</b><br/>Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998 .).<br /><br /><small>N Engl J Med: 26 Aug 2012; epub ahead of print</small></div>
Roe MT, Armstrong PW, Fox KA, White HD, ... Ohman EM, the TRILOGY ACS Investigators
N Engl J Med: 26 Aug 2012; epub ahead of print | PMID: 22920930
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<div><h4>Paclitaxel-Eluting versus Everolimus-Eluting Coronary Stents in Diabetes.</h4><i>Kaul U, Bangalore S, Seth A, Arambam P, ... Bahuleyan CG, TUXEDO–India Investigators</i><br /><b>Background:</b><br/>The choice of drug-eluting stent in the treatment of patients with diabetes mellitus and coronary artery disease who are undergoing percutaneous coronary intervention (PCI) has been debated. Previous studies comparing paclitaxel-eluting stents with stents eluting rapamycin (now called sirolimus) or its analogues (everolimus or zotarolimus) have produced contradictory results, ranging from equivalence between stent types to superiority of everolimus-eluting stents. Methods We randomly assigned 1830 patients with diabetes mellitus and coronary artery disease who were undergoing PCI to receive either a paclitaxel-eluting stent or an everolimus-eluting stent. We used a noninferiority trial design with a noninferiority margin of 4 percentage points for the upper boundary of the 95% confidence interval of the risk difference. The primary end point was target-vessel failure, which was defined as a composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization at the 1-year follow-up. Results At 1 year, paclitaxel-eluting stents did not meet the criterion for noninferiority to everolimus-eluting stents with respect to the primary end point (rate of target-vessel failure, 5.6% vs. 2.9%; risk difference, 2.7 percentage points [95% confidence interval, 0.8 to 4.5]; relative risk, 1.89 [95% confidence interval, 1.20 to 2.99]; P=0.38 for noninferiority). There was a significantly higher 1-year rate in the paclitaxel-eluting stent group than in the everolimus-eluting stent group of target-vessel failure (P=0.005), spontaneous myocardial infarction (3.2% vs. 1.2%, P=0.004), stent thrombosis (2.1% vs. 0.4%, P=0.002), target-vessel revascularization (3.4% vs. 1.2%, P=0.002), and target-lesion revascularization (3.4% vs. 1.2%, P=0.002). <br /><b>Conclusions:</b><br/>In patients with diabetes mellitus and coronary artery disease undergoing PCI, paclitaxel-eluting stents were not shown to be noninferior to everolimus-eluting stents, and they resulted in higher rates of target-vessel failure, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. (Funded by Boston Scientific; TUXEDO-India Clinical Trials Registry-India number, CTRI/2011/06/001830 ).<br /><br /><small>N Engl J Med: 13 Oct 2015; epub ahead of print</small></div>
Kaul U, Bangalore S, Seth A, Arambam P, ... Bahuleyan CG, TUXEDO–India Investigators
N Engl J Med: 13 Oct 2015; epub ahead of print | PMID: 26466202
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<div><h4>Reduction in Inappropriate Therapy and Mortality through ICD Programming.</h4><i>Moss AJ, Schuger C, Beck CA, Brown MW, ... Zareba W, the MADIT-RIT Trial Investigators</i><br /><b>Background:</b><br/>The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects. Methods We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ≥200 beats per minute). Results During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval [CI], 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups. <br /><b>Conclusions:</b><br/>Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310 .).<br /><br /><small>N Engl J Med: 06 Nov 2012; epub ahead of print</small></div>
Moss AJ, Schuger C, Beck CA, Brown MW, ... Zareba W, the MADIT-RIT Trial Investigators
N Engl J Med: 06 Nov 2012; epub ahead of print | PMID: 23131066
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<div><h4>n-3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia.</h4><i>The ORIGIN Trial Investigators</i><br /><b>Background:</b><br/>The use of n-3 fatty acids may prevent cardiovascular events in patients with recent myocardial infarction or heart failure. Their effects in patients with (or at risk for) type 2 diabetes mellitus are unknown. Methods In this double-blind study with a 2-by-2 factorial design, we randomly assigned 12,536 patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes to receive a 1-g capsule containing at least 900 mg (90% or more) of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin glargine or standard care. The primary outcome was death from cardiovascular causes. The results of the comparison between n-3 fatty acids and placebo are reported here. Results During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n-3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72). The use of n-3 fatty acids also had no significant effect on the rates of major vascular events (1034 patients [16.5%] vs. 1017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P=0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P=0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P=0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n-3 fatty acids than among those receiving placebo (P<0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups. <br /><b>Conclusions:</b><br/>Daily supplementation with 1 g of n-3 fatty acids did not reduce the rate of cardiovascular events in patients at high risk for cardiovascular events. (Funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784 .).<br /><br /><small>N Engl J Med: 11 Jun 2012; epub ahead of print</small></div>
The ORIGIN Trial Investigators
N Engl J Med: 11 Jun 2012; epub ahead of print | PMID: 22686415
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<div><h4>Effect of Two Intensive Statin Regimens on Progression of Coronary Disease.</h4><i>Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, ... Wolski K, Nissen SE</i><br /><b>Background:</b><br/> Statins reduce adverse cardiovascular outcomes and slow the progression of coronary atherosclerosis in proportion to their ability to reduce low-density lipoprotein (LDL) cholesterol. However, few studies have either assessed the ability of intensive statin treatments to achieve disease regression or compared alternative approaches to maximal statin administration. Methods We performed serial intravascular ultrasonography in 1039 patients with coronary disease, at baseline and after 104 weeks of treatment with either atorvastatin, 80 mg daily, or rosuvastatin, 40 mg daily, to compare the effect of these two intensive statin regimens on the progression of coronary atherosclerosis, as well as to assess their safety and side-effect profiles. Results After 104 weeks of therapy, the rosuvastatin group had lower levels of LDL cholesterol than the atorvastatin group (62.6 vs. 70.2 mg per deciliter [1.62 vs. 1.82 mmol per liter], P<0.001), and higher levels of high-density lipoprotein (HDL) cholesterol (50.4 vs. 48.6 mg per deciliter [1.30 vs. 1.26 mmol per liter], P=0.01). The primary efficacy end point, percent atheroma volume (PAV), decreased by 0.99% (95% confidence interval [CI], -1.19 to -0.63) with atorvastatin and by 1.22% (95% CI, -1.52 to -0.90) with rosuvastatin (P=0.17). The effect on the secondary efficacy end point, normalized total atheroma volume (TAV), was more favorable with rosuvastatin than with atorvastatin: -6.39 mm(3) (95% CI, -7.52 to -5.12), as compared with -4.42 mm(3) (95% CI, -5.98 to -3.26) (P=0.01). Both agents induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for PAV (P=0.07) and 64.7% and 71.3%, respectively, for TAV (P=0.02). Both agents had acceptable side-effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events. <br /><b>Conclusions:</b><br/> Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups. (Funded by AstraZeneca Pharmaceuticals; ClinicalTrials.gov number, NCT000620542 .).<br /><br /><small>N Engl J Med: 16 Nov 2011; epub ahead of print</small></div>
Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, ... Wolski K, Nissen SE
N Engl J Med: 16 Nov 2011; epub ahead of print | PMID: 22085316
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<div><h4>Trial of Early, Goal-Directed Resuscitation for Septic Shock.</h4><i>Mouncey PR, Osborn TM, Power GS, Harrison DA, ... Rowan KM, ProMISe Trial Investigators</i><br /><b>Background:</b><br/>Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. Methods We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. Results We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. <br /><b>Conclusions:</b><br/>In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479 .).<br /><br /><small>N Engl J Med: 16 Mar 2015; epub ahead of print</small></div>
Mouncey PR, Osborn TM, Power GS, Harrison DA, ... Rowan KM, ProMISe Trial Investigators
N Engl J Med: 16 Mar 2015; epub ahead of print | PMID: 25776532
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<div><h4>Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events.</h4><i>Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, ... Stein EA, Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators</i><br /><b>Background:</b><br/>Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. Methods In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. Results As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). <br /><b>Conclusions:</b><br/>During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918 .).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, ... Stein EA, Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25773607
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<div><h4>Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents.</h4><i>Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, ... Massaro JM, the DAPT Study Investigators</i><br /><b>Background:</b><br/>Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain. Methods Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding. Results A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. <br /><b>Conclusions:</b><br/>Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938 .).<br /><br /><small>N Engl J Med: 16 Nov 2014; epub ahead of print</small></div>
Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, ... Massaro JM, the DAPT Study Investigators
N Engl J Med: 16 Nov 2014; epub ahead of print | PMID: 25399658
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<div><h4>Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease.</h4><i>The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute</i><br /><b>Background:</b><br/>Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). <br /><b>Conclusions:</b><br/>Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).<br /><br /><small>N Engl J Med: 17 Jun 2014; epub ahead of print</small></div>
The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute
N Engl J Med: 17 Jun 2014; epub ahead of print | PMID: 24941081
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Abstract
<div><h4>Clonidine in Patients Undergoing Noncardiac Surgery.</h4><i>Devereaux PJ, Sessler DI, Leslie K, Kurz A, ... Yusuf S, the POISE-2 Investigators</i><br /><b>Background:</b><br/>Marked activation of the sympathetic nervous system occurs during and after noncardiac surgery. Low-dose clonidine, which blunts central sympathetic outflow, may prevent perioperative myocardial infarction and death without inducing hemodynamic instability. Methods We performed a blinded, randomized trial with a 2-by-2 factorial design to allow separate evaluation of low-dose clonidine versus placebo and low-dose aspirin versus placebo in patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. A total of 10,010 patients at 135 centers in 23 countries were enrolled. For the comparison of clonidine with placebo, patients were randomly assigned to receive clonidine (0.2 mg per day) or placebo just before surgery, with the study drug continued until 72 hours after surgery. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. Results Clonidine, as compared with placebo, did not reduce the number of primary-outcome events (367 and 339, respectively; hazard ratio with clonidine, 1.08; 95% confidence interval [CI], 0.93 to 1.26; P=0.29). Myocardial infarction occurred in 329 patients (6.6%) assigned to clonidine and in 295 patients (5.9%) assigned to placebo (hazard ratio, 1.11; 95% CI, 0.95 to 1.30; P=0.18). Significantly more patients in the clonidine group than in the placebo group had clinically important hypotension (2385 patients [47.6%] vs. 1854 patients [37.1%]; hazard ratio 1.32; 95% CI, 1.24 to 1.40; P<0.001). Clonidine, as compared with placebo, was associated with an increased rate of nonfatal cardiac arrest (0.3% [16 patients] vs. 0.1% [5 patients]; hazard ratio, 3.20; 95% CI, 1.17 to 8.73; P=0.02). <br /><b>Conclusions:</b><br/>Administration of low-dose clonidine in patients undergoing noncardiac surgery did not reduce the rate of the composite outcome of death or nonfatal myocardial infarction; it did, however, increase the risk of clinically important hypotension and nonfatal cardiac arrest. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874 .).<br /><br /><small>N Engl J Med: 30 Mar 2014; epub ahead of print</small></div>
Devereaux PJ, Sessler DI, Leslie K, Kurz A, ... Yusuf S, the POISE-2 Investigators
N Engl J Med: 30 Mar 2014; epub ahead of print | PMID: 24679061
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