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<div><h4>Glycogenin-1 deficiency and inactivated priming of glycogen synthesis.</h4><i>Moslemi AR, Lindberg C, Nilsson J, Tajsharghi H, Andersson B, Oldfors A</i><br />Glycogen, which serves as a major energy reserve in cells, is a large, branched polymer of glucose molecules. We describe a patient who had muscle weakness, associated with the depletion of glycogen in skeletal muscle, and cardiac arrhythmia, associated with the accumulation of abnormal storage material in the heart. The skeletal muscle showed a marked predominance of slow-twitch, oxidative muscle fibers and mitochondrial proliferation. Western blotting showed the presence of unglucosylated glycogenin-1 in the muscle and heart. Sequencing of the glycogenin-1 gene, GYG1, revealed a nonsense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle. Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 01 Apr 2010; 362:1203-10</small></div>
Moslemi AR, Lindberg C, Nilsson J, Tajsharghi H, Andersson B, Oldfors A
N Engl J Med: 01 Apr 2010; 362:1203-10 | PMID: 20357282
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<div><h4>Percutaneous Repair or Surgery for Mitral Regurgitation.</h4><i>Feldman T, Foster E, Glower DG, Kar S, ... Mauri L, the EVEREST II Investigators</i><br /><b>Background:</b><br/>Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet. Methods We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days. Results At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline. <br /><b>Conclusions:</b><br/>Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274 .).<br /><br /><small>N Engl J Med: 05 Apr 2011; epub ahead of print</small></div>
Feldman T, Foster E, Glower DG, Kar S, ... Mauri L, the EVEREST II Investigators
N Engl J Med: 05 Apr 2011; epub ahead of print | PMID: 21463154
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<div><h4>An Entirely Subcutaneous Implantable Cardioverter-Defibrillator.</h4><i>Bardy GH, Smith WM, Hood MA, Crozier IG, ... Cappato R, Grace AA</i><br />BACKGROUND: Implantable cardioverter-defibrillators (ICDs) prevent sudden death from cardiac causes in selected patients but require the use of transvenous lead systems. To eliminate the need for venous access, we designed and tested an entirely subcutaneous ICD system. <br /><b>Methods:</b><br/>First, we conducted two short-term clinical trials to identify a suitable device configuration and assess energy requirements. We evaluated four subcutaneous ICD configurations in 78 patients who were candidates for ICD implantation and subsequently tested the best configuration in 49 additional patients to determine the subcutaneous defibrillation threshold in comparison with that of the standard transvenous ICD. Then we evaluated the long-term use of subcutaneous ICDs in a pilot study, involving 6 patients, which was followed by a trial involving 55 patients. <br /><b>Results:</b><br/>The best device configuration consisted of a parasternal electrode and a left lateral thoracic pulse generator. This configuration was as effective as a transvenous ICD for terminating induced ventricular fibrillation, albeit with a significantly higher mean (+/-SD) energy requirement (36.6+/-19.8 J vs. 11.1+/-8.5 J). Among patients who received a permanent subcutaneous ICD, ventricular fibrillation was successfully detected in 100% of 137 induced episodes. Induced ventricular fibrillation was converted twice in 58 of 59 patients (98%) with the delivery of 65-J shocks in two consecutive tests. Clinically significant adverse events included two pocket infections and four lead revisions. After a mean of 10+/-1 months, the device had successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. <br /><b>Conclusions:</b><br/>In small, nonrandomized studies, an entirely subcutaneous ICD consistently detected and converted ventricular fibrillation induced during electrophysiological testing. The device also successfully detected and treated all 12 episodes of spontaneous, sustained ventricular tachyarrhythmia. (ClinicalTrials.gov numbers, NCT00399217 and NCT00853645.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 13 May 2010; epub ahead of print</small></div>
Bardy GH, Smith WM, Hood MA, Crozier IG, ... Cappato R, Grace AA
N Engl J Med: 13 May 2010; epub ahead of print | PMID: 20463331
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<div><h4>Apixaban in Patients with Atrial Fibrillation.</h4><i>Connolly SJ, Eikelboom J, Joyner C, Diener HC, ... Yusuf S, the AVERROES Steering Committee and Investigators</i><br /><b>Background:</b><br/>Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. Methods In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. Results Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. <br /><b>Conclusions:</b><br/>In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769 .).<br /><br /><small>N Engl J Med: 11 Feb 2011; epub ahead of print</small></div>
Connolly SJ, Eikelboom J, Joyner C, Diener HC, ... Yusuf S, the AVERROES Steering Committee and Investigators
N Engl J Med: 11 Feb 2011; epub ahead of print | PMID: 21309657
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<div><h4>Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction.</h4><i>Bonow RO, Maurer G, Lee KL, Holly TA, ... Panza AJ, the STICH Trial Investigators</i><br /><b>Background:</b><br/>The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. Methods In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. Results Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). <br /><b>Conclusions:</b><br/>The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595 .).<br /><br /><small>N Engl J Med: 05 Apr 2011; epub ahead of print</small></div>
Bonow RO, Maurer G, Lee KL, Holly TA, ... Panza AJ, the STICH Trial Investigators
N Engl J Med: 05 Apr 2011; epub ahead of print | PMID: 21463153
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<div><h4>Drug-Eluting versus Bare-Metal Stents in Large Coronary Arteries.</h4><i>Kaiser C, Galatius S, Erne P, Eberli F, ... Pfisterer M, the BASKET–PROVE Study Group</i><br /><b>Background:</b><br/>Recent data have suggested that patients with coronary disease in large arteries are at increased risk for late cardiac events after percutaneous intervention with first-generation drug-eluting stents, as compared with bare-metal stents. We sought to confirm this observation and to assess whether this increase in risk was also seen with second-generation drug-eluting stents. Methods We randomly assigned 2314 patients needing stents that were 3.0 mm or more in diameter to receive sirolimus-eluting, everolimus-eluting, or bare-metal stents. The primary end point was the composite of death from cardiac causes or nonfatal myocardial infarction at 2 years. Late events (occurring during months 7 to 24) and target-vessel revascularization were the main secondary end points. Results The rates of the primary end point were 2.6% among patients receiving sirolimus-eluting stents, 3.2% among those receiving everolimus-eluting stents, and 4.8% among those receiving bare-metal stents, with no significant differences between patients receiving either drug-eluting stent and those receiving bare-metal stents. There were also no significant between-group differences in the rate of late events or in the rate of death, myocardial infarction, or stent thrombosis. Rates of target-vessel revascularization for reasons unrelated to myocardial infarction were 3.7% among patients receiving sirolimus-eluting stents, 3.1% among those receiving everolimus-eluting stents, and 8.9% among those receiving bare-metal stents. The rate of target-vessel revascularization was significantly reduced among patients receiving either drug-eluting stent, as compared with a bare-metal stent, with no significant difference between the two types of drug-eluting stents. <br /><b>Conclusions:</b><br/>In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen. (Funded by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research; Current Controlled Trials number, ISRCTN72444640.).<br /><br /><small>N Engl J Med: 17 Nov 2010; epub ahead of print</small></div>
Kaiser C, Galatius S, Erne P, Eberli F, ... Pfisterer M, the BASKET–PROVE Study Group
N Engl J Med: 17 Nov 2010; epub ahead of print | PMID: 21080780
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<div><h4>Randomized Trial of Stents versus Bypass Surgery for Left Main Coronary Artery Disease.</h4><i>Park SJ, Kim YH, Park DW, Yun SC, ... Tahk SJ, Seung KB</i><br /><b>Background:</b><br/>Percutaneous coronary intervention (PCI) is increasingly used to treat unprotected left main coronary artery stenosis, although coronary-artery bypass grafting (CABG) has been considered to be the treatment of choice. Methods We randomly assigned patients with unprotected left main coronary artery stenosis to undergo CABG (300 patients) or PCI with sirolimus-eluting stents (300 patients). Using a wide margin for noninferiority, we compared the groups with respect to the primary composite end point of major adverse cardiac or cerebrovascular events (death from any cause, myocardial infarction, stroke, or ischemia-driven target-vessel revascularization) at 1 year. Event rates at 2 years were also compared between the two groups. Results The primary end point occurred in 26 patients assigned to PCI as compared with 20 patients assigned to CABG (cumulative event rate, 8.7% vs. 6.7%; absolute risk difference, 2.0 percentage points; 95% confidence interval [CI], -1.6 to 5.6; P=0.01 for noninferiority). By 2 years, the primary end point had occurred in 36 patients in the PCI group as compared with 24 in the CABG group (cumulative event rate, 12.2% vs. 8.1%; hazard ratio with PCI, 1.50; 95% CI, 0.90 to 2.52; P=0.12). The composite rate of death, myocardial infarction, or stroke at 2 years occurred in 13 and 14 patients in the two groups, respectively (cumulative event rate, 4.4% and 4.7%, respectively; hazard ratio, 0.92; 95% CI, 0.43 to 1.96; P=0.83). Ischemia-driven target-vessel revascularization occurred in 26 patients in the PCI group as compared with 12 patients in the CABG group (cumulative event rate, 9.0% vs. 4.2%; hazard ratio, 2.18; 95% CI, 1.10 to 4.32; P=0.02). <br /><b>Conclusions:</b><br/>In this randomized trial involving patients with unprotected left main coronary artery stenosis, PCI with sirolimus-eluting stents was shown to be noninferior to CABG with respect to major adverse cardiac or cerebrovascular events. However, the noninferiority margin was wide, and the results cannot be considered clinically directive. (Funded by the Cardiovascular Research Foundation, Seoul, Korea, and others; PRECOMBAT ClinicalTrials.gov number, NCT00422968 .).<br /><br /><small>N Engl J Med: 05 Apr 2011; epub ahead of print</small></div>
Park SJ, Kim YH, Park DW, Yun SC, ... Tahk SJ, Seung KB
N Engl J Med: 05 Apr 2011; epub ahead of print | PMID: 21463149
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<div><h4>Public reporting of discharge planning and rates of readmissions.</h4><i>Jha AK, Orav EJ, Epstein AM</i><br />BACKGROUND: A reduction in hospital readmissions may improve quality and reduce costs. The Centers for Medicare and Medicaid Services has initiated a national effort to measure and publicly report on the conduct of discharge planning. We know little about how U.S. hospitals perform on the current discharge metrics, the factors that underlie better performance, and whether better performance is related to lower readmission rates. <br /><b>Methods:</b><br/>We examined hospital performance on the basis of two measures of discharge planning: the adequacy of documentation in the chart that discharge instructions were provided to patients with congestive heart failure, and patient-reported experiences with discharge planning. We examined the association between performance on these measures and rates of readmission for congestive heart failure and pneumonia. <br /><b>Results:</b><br/>We found a weak correlation in performance between the two discharge measures (r=0.05, P<0.001). Although larger hospitals performed better on the chart-based measure, smaller hospitals and those with higher nurse-staffing levels performed better on the patient-reported measure. We found no association between performance on the chart-based measure and readmission rates among patients with congestive heart failure (readmission rates among hospitals performing in the highest quartile vs. the lowest quartile, 23.7% vs. 23.5%; P=0.54) and only a very modest association between performance on the patient-reported measure and readmission rates for congestive heart failure (readmission rates among hospitals performing in the highest quartile vs. the lowest quartile, 22.4% vs. 24.7%; P<0.001) and pneumonia (17.5% vs. 19.5%, P<0.001). <br /><b>Conclusions:</b><br/>Our findings suggest that current efforts to collect and publicly report data on discharge planning are unlikely to yield large reductions in unnecessary readmissions.<br /><br /><small>N Engl J Med: 31 Dec 2009; 361:2637-45</small></div>
Jha AK, Orav EJ, Epstein AM
N Engl J Med: 31 Dec 2009; 361:2637-45 | PMID: 20042755
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<div><h4>Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease.</h4><i>Stone GW, Rizvi A, Newman W, Mastali K, ... Kereiakes DJ, SPIRIT IV Investigators</i><br />BACKGROUND: Previous studies have established the superiority of coronary everolimus-eluting stents over paclitaxel-eluting stents with respect to angiographic findings. However, these trials were not powered for superiority in clinical end points. <br /><b>Methods:</b><br/>We randomly assigned 3687 patients at 66 U.S. sites to receive everolimus-eluting stents or paclitaxel-eluting stents without routine follow-up angiography. The primary end point was the 1-year composite rate of target-lesion failure (defined as cardiac death, target-vessel myocardial infarction, or ischemia-driven target-lesion revascularization). <br /><b>Results:</b><br/>Everolimus-eluting stents were superior to paclitaxel-eluting stents with respect to the primary end point of target-lesion failure (4.2% vs. 6.8%; relative risk, 0.62; 95% confidence interval, 0.46 to 0.82; P=0.001). Everolimus-eluting stents were also superior with respect to the major secondary end point of the 1-year rate of ischemia-driven target-lesion revascularization (P=0.001) and were noninferior with respect to the major secondary end point of the 1-year composite rate of cardiac death or target-vessel myocardial infarction (P<0.001 for noninferiority; P=0.09 for superiority). The 1-year rates of myocardial infarction and stent thrombosis were also lower with everolimus-eluting stents than with paclitaxel-eluting stents (1.9% vs. 3.1%, P=0.02 for myocardial infarction; 0.17% vs. 0.85%, P=0.004 for stent thrombosis). Target-lesion failure was consistently reduced with everolimus-eluting stents as compared with paclitaxel-eluting stents in 12 prespecified subgroups, except in the subgroup of patients with diabetes (6.4% vs. 6.9%, P=0.80). <br /><b>Conclusions:</b><br/>Everolimus-eluting stents, as compared with paclitaxel-eluting stents, resulted in reduced rates of target-lesion failure at 1 year, results that were consistent in all patients except those with diabetes, in whom the results were nonsignificantly different. (ClinicalTrials.gov number, NCT00307047.)<br /><br /><small>N Engl J Med: 06 May 2010; 362:1663-74</small></div>
Stone GW, Rizvi A, Newman W, Mastali K, ... Kereiakes DJ, SPIRIT IV Investigators
N Engl J Med: 06 May 2010; 362:1663-74 | PMID: 20445180
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<div><h4>Cardiac-Resynchronization Therapy for Mild-to-Moderate Heart Failure.</h4><i>Tang AS, Wells GA, Talajic M, Arnold MO, ... Rouleau JL, the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) Investigators</i><br /><b>Background:</b><br/>Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients. Methods We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure. Results We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P=0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001). <br /><b>Conclusions:</b><br/>Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).<br /><br /><small>N Engl J Med: 15 Nov 2010; epub ahead of print</small></div>
Tang AS, Wells GA, Talajic M, Arnold MO, ... Rouleau JL, the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) Investigators
N Engl J Med: 15 Nov 2010; epub ahead of print | PMID: 21073365
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<div><h4>A sensitive cardiac troponin T assay in stable coronary artery disease.</h4><i>Omland T, de Lemos JA, Sabatine MS, Christophi CA, ... Braunwald E, </i><br />BACKGROUND: In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown. <br /><b>Methods:</b><br/>We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years. <br /><b>Results:</b><br/>With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 microg per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 microg per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death (adjusted hazard ratio per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60 to 2.74; P<0.001) and of heart failure (adjusted hazard ratio, 2.20; 95% CI, 1.66 to 2.90; P<0.001) in this study group. Increased risk associated with higher levels of troponin T was evident well below the limit of detection of conventional cardiac troponin T assays and below the 99th percentile of values in a healthy population. There was no association between troponin T levels as measured with the highly sensitive assay and the incidence of myocardial infarction (adjusted hazard ratio, 1.16; 95% CI, 0.97 to 1.40; P=0.11). <br /><b>Conclusions:</b><br/>After adjustment for other independent prognostic indicators, cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease.<br /><br /><small>N Engl J Med: 24 Dec 2009; 361:2538-47</small></div>
Omland T, de Lemos JA, Sabatine MS, Christophi CA, ... Braunwald E,
N Engl J Med: 24 Dec 2009; 361:2538-47 | PMID: 19940289
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<div><h4>Telemonitoring in Patients with Heart Failure.</h4><i>Chaudhry SI, Mattera JA, Curtis JP, Spertus JA, ... Cooper LS, Krumholz HM</i><br /><b>Background:</b><br/>Small studies suggest that telemonitoring may improve heart-failure outcomes, but its effect in a large trial has not been established. Methods We randomly assigned 1653 patients who had recently been hospitalized for heart failure to undergo either telemonitoring (826 patients) or usual care (827 patients). Telemonitoring was accomplished by means of a telephone-based interactive voice-response system that collected daily information about symptoms and weight that was reviewed by the patients\' clinicians. The primary end point was readmission for any reason or death from any cause within 180 days after enrollment. Secondary end points included hospitalization for heart failure, number of days in the hospital, and number of hospitalizations. Results The median age of the patients was 61 years; 42.0% were female, and 39.0% were black. The telemonitoring group and the usual-care group did not differ significantly with respect to the primary end point, which occurred in 52.3% and 51.5% of patients, respectively (difference, 0.8 percentage points; 95% confidence interval [CI], -4.0 to 5.6; P=0.75 by the chi-square test). Readmission for any reason occurred in 49.3% of patients in the telemonitoring group and 47.4% of patients in the usual-care group (difference, 1.9 percentage points; 95% CI, -3.0 to 6.7; P=0.45 by the chi-square test). Death occurred in 11.1% of the telemonitoring group and 11.4% of the usual care group (difference, -0.2 percentage points; 95% CI, -3.3 to 2.8; P=0.88 by the chi-square test). There were no significant differences between the two groups with respect to the secondary end points or the time to the primary end point or its components. No adverse events were reported. <br /><b>Conclusions:</b><br/>Among patients recently hospitalized for heart failure, telemonitoring did not improve outcomes. The results indicate the importance of a thorough, independent evaluation of disease-management strategies before their adoption. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00303212.).<br /><br /><small>N Engl J Med: 17 Nov 2010; epub ahead of print</small></div>
Chaudhry SI, Mattera JA, Curtis JP, Spertus JA, ... Cooper LS, Krumholz HM
N Engl J Med: 17 Nov 2010; epub ahead of print | PMID: 21080835
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<div><h4>Long-term outcome associated with early repolarization on electrocardiography.</h4><i>Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, ... Reunanen A, Huikuri HV</i><br />BACKGROUND: Early repolarization, which is characterized by an elevation of the QRS-ST junction (J point) in leads other than V(1) through V(3) on 12-lead electrocardiography, has been associated with vulnerability to ventricular fibrillation, but little is known about the prognostic significance of this pattern in the general population. <br /><b>Methods:</b><br/>We assessed the prevalence and prognostic significance of early repolarization on 12-lead electrocardiography in a community-based general population of 10,864 middle-aged subjects (mean [+/-SD] age, 44+/-8 years). The primary end point was death from cardiac causes, and secondary end points were death from any cause and death from arrhythmia during a mean follow-up of 30+/-11 years. Early repolarization was stratified according to the degree of J-point elevation (> or = 0.1 mV or > 0.2 mV) in either inferior or lateral leads. <br /><b>Results:</b><br/>The early-repolarization pattern of 0.1 mV or more was present in 630 subjects (5.8%): 384 (3.5%) in inferior leads and 262 (2.4%) in lateral leads, with elevations in both leads in 16 subjects (0.1%). J-point elevation of at least 0.1 mV in inferior leads was associated with an increased risk of death from cardiac causes (adjusted relative risk, 1.28; 95% confidence interval [CI], 1.04 to 1.59; P=0.03); 36 subjects (0.3%) with J-point elevation of more than 0.2 mV in inferior leads had a markedly elevated risk of death from cardiac causes (adjusted relative risk, 2.98; 95% CI, 1.85 to 4.92; P<0.001) and from arrhythmia (adjusted relative risk, 2.92; 95% CI, 1.45 to 5.89; P=0.01). Other electrocardiographic risk markers, such as a prolonged QT interval corrected for heart rate (P=0.03) and left ventricular hypertrophy (P=0.004), were weaker predictors of the primary end point. <br /><b>Conclusions:</b><br/>An early-repolarization pattern in the inferior leads of a standard electrocardiogram is associated with an increased risk of death from cardiac causes in middle-aged subjects.<br /><br /><small>N Engl J Med: 24 Dec 2009; 361:2529-37</small></div>
Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, ... Reunanen A, Huikuri HV
N Engl J Med: 24 Dec 2009; 361:2529-37 | PMID: 19917913
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<div><h4>Exome Sequencing, ANGPTL3 Mutations, and Familial Combined Hypolipidemia.</h4><i>Musunuru K, Pirruccello JP, Do R, Peloso GM, ... Yue P, Kathiresan S</i><br />We sequenced all protein-coding regions of the genome (the “exome”) in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).<br /><br /><small>N Engl J Med: 14 Oct 2010; epub ahead of print</small></div>
Musunuru K, Pirruccello JP, Do R, Peloso GM, ... Yue P, Kathiresan S
N Engl J Med: 14 Oct 2010; epub ahead of print | PMID: 20942659
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<div><h4>Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events.</h4><i>The NAVIGATOR Study Group</i><br />BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. <br /><b>Methods:</b><br/>In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. <br /><b>Results:</b><br/>The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). <br /><b>Conclusions:</b><br/>Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (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: 20228403
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<div><h4>CPAP for the Metabolic Syndrome in Patients with Obstructive Sleep Apnea.</h4><i>Sharma SK, Agrawal S, Damodaran D, Sreenivas V, ... Jagia P, Kumar A</i><br /><b>Background:</b><br/> Obstructive sleep apnea is associated with an increased prevalence of the metabolic syndrome and its components. It is unclear whether treatment of obstructive sleep apnea syndrome with continuous positive airway pressure (CPAP) would modify these outcomes. Methods In our double-blind, placebo-controlled trial, we randomly assigned patients with obstructive sleep apnea syndrome to undergo 3 months of therapeutic CPAP followed by 3 months of sham CPAP, or vice versa, with a washout period of 1 month in between. Before and after each intervention, we obtained measurements of anthropometric variables, blood pressure, fasting blood glucose levels, insulin resistance (with the use of homeostasis model assessment), fasting blood lipid profile, glycated hemoglobin levels, carotid intima-media thickness, and visceral fat. The metabolic syndrome was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria, with Asian cutoff values for abdominal obesity. Results A total of 86 patients completed the study, 75 (87%) of whom had the metabolic syndrome. CPAP treatment (vs. sham CPAP) was associated with significant mean decreases in systolic blood pressure (3.9 mm Hg; 95% confidence interval [CI], 1.4 to 6.4; P=0.001), diastolic blood pressure (2.5 mm Hg; 95% CI, 0.9 to 4.1; P<0.001), serum total cholesterol (13.3 mg per deciliter; 95% CI, 5.3 to 21.3; P=0.005), non-high-density lipoprotein cholesterol (13.3 mg per deciliter; 95% CI, 4.8 to 21.8; P=0.009), low-density lipoprotein cholesterol (9.6 mg per deciliter; 95% CI, 2.5 to 16.7; P=0.008), triglycerides (18.7 mg per deciliter; 95% CI, 4.3 to 41.6; P=0.02), and glycated hemoglobin (0.2%; 95% CI, 0.1 to 0.4; P=0.003). The frequency of the metabolic syndrome was reduced after CPAP therapy (reversal found in 11 of 86 patients [13%] undergoing CPAP therapy vs. 1 of 86 [1%] undergoing sham CPAP). Accelerated hypertension developed 1 patient receiving CPAP therapy first, intolerance to CPAP developed in 2 others, and another patient declined to continue sham CPAP. <br /><b>Conclusions:</b><br/> In patients with moderate-to-severe obstructive sleep apnea syndrome, 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities. (Funded by Pfizer; ClinicalTrials.gov number, NCT00694616 .).<br /><br /><small>N Engl J Med: 15 Dec 2011; 365:2277-86</small></div>
Sharma SK, Agrawal S, Damodaran D, Sreenivas V, ... Jagia P, Kumar A
N Engl J Med: 15 Dec 2011; 365:2277-86 | PMID: 22168642
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<div><h4>Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease.</h4><i>Cannon CP, Shah S, Dansky HM, Davidson M, ... Barter P, the DEFINE Investigators</i><br /><b>Background:</b><br/>Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol. Methods We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated. Results A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001) - a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001) - a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P=0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib. <br /><b>Conclusions:</b><br/>Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).<br /><br /><small>N Engl J Med: 18 Nov 2010; epub ahead of print</small></div>
Cannon CP, Shah S, Dansky HM, Davidson M, ... Barter P, the DEFINE Investigators
N Engl J Med: 18 Nov 2010; epub ahead of print | PMID: 21082868
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<div><h4>Childhood Adiposity, Adult Adiposity, and Cardiovascular Risk Factors.</h4><i>Juonala M, Magnussen CG, Berenson GS, Venn A, ... Dwyer T, Raitakari OT</i><br /><b>Background:</b><br/> Obesity in childhood is associated with increased cardiovascular risk. It is uncertain whether this risk is attenuated in persons who are overweight or obese as children but not obese as adults. Methods We analyzed data from four prospective cohort studies that measured childhood and adult body-mass index (BMI, the weight in kilograms divided by the square of the height in meters). The mean length of follow-up was 23 years. To define high adiposity status, international age-specific and sex-specific BMI cutoff points for overweight and obesity were used for children, and a BMI cutoff point of 30 was used for adults. Results Data were available for 6328 subjects. Subjects with consistently high adiposity status from childhood to adulthood, as compared with persons who had a normal BMI as children and were nonobese as adults, had an increased risk of type 2 diabetes (relative risk, 5.4; 95% confidence interval [CI], 3.4 to 8.5), hypertension (relative risk, 2.7; 95% CI, 2.2 to 3.3), elevated low-density lipoprotein cholesterol levels (relative risk, 1.8; 95% CI, 1.4 to 2.3), reduced high-density lipoprotein cholesterol levels (relative risk, 2.1; 95% CI, 1.8 to 2.5), elevated triglyceride levels (relative risk, 3.0; 95% CI, 2.4 to 3.8), and carotid-artery atherosclerosis (increased intima-media thickness of the carotid artery) (relative risk, 1.7; 95% CI, 1.4 to 2.2) (P≤0.002 for all comparisons). Persons who were overweight or obese during childhood but were nonobese as adults had risks of the outcomes that were similar to those of persons who had a normal BMI consistently from childhood to adulthood (P>0.20 for all comparisons). <br /><b>Conclusions:</b><br/> Overweight or obese children who were obese as adults had increased risks of type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. The risks of these outcomes among overweight or obese children who became nonobese by adulthood were similar to those among persons who were never obese. (Funded by the Academy of Finland and others.).<br /><br /><small>N Engl J Med: 17 Nov 2011; 365:1876-1885</small></div>
Juonala M, Magnussen CG, Berenson GS, Venn A, ... Dwyer T, Raitakari OT
N Engl J Med: 17 Nov 2011; 365:1876-1885 | PMID: 22087679
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<div><h4>Advanced heart failure treated with continuous-flow left ventricular assist device.</h4><i>Slaughter MS, Rogers JG, Milano CA, Russell SD, ... Frazier OH, </i><br />BACKGROUND: Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. <br /><b>Methods:</b><br/>In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuous-flow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity. <br /><b>Results:</b><br/>Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups. <br /><b>Conclusions:</b><br/>Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)<br /><br /><small>N Engl J Med: 03 Dec 2009; 361:2241-51</small></div>
Slaughter MS, Rogers JG, Milano CA, Russell SD, ... Frazier OH,
N Engl J Med: 03 Dec 2009; 361:2241-51 | PMID: 19920051
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<div><h4>Comparative Effectiveness of Weight-Loss Interventions in Clinical Practice.</h4><i>Appel LJ, Clark JM, Yeh HC, Wang NY, ... Louis TA, Brancati FL</i><br /><b>Background:</b><br/> Obesity and its cardiovascular complications are extremely common medical problems, but evidence on how to accomplish weight loss in clinical practice is sparse. Methods We conducted a randomized, controlled trial to examine the effects of two behavioral weight-loss interventions in 415 obese patients with at least one cardiovascular risk factor. Participants were recruited from six primary care practices; 63.6% were women, 41.0% were black, and the mean age was 54.0 years. One intervention provided patients with weight-loss support remotely - through the telephone, a study-specific Web site, and e-mail. The other intervention provided in-person support during group and individual sessions, along with the three remote means of support. There was also a control group in which weight loss was self-directed. Outcomes were compared between each intervention group and the control group and between the two intervention groups. For both interventions, primary care providers reinforced participation at routinely scheduled visits. The trial duration was 24 months. Results At baseline, the mean body-mass index (the weight in kilograms divided by the square of the height in meters) for all participants was 36.6, and the mean weight was 103.8 kg. At 24 months, the mean change in weight from baseline was -0.8 kg in the control group, -4.6 kg in the group receiving remote support only (P<0.001 for the comparison with the control group), and -5.1 kg in the group receiving in-person support (P<0.001 for the comparison with the control group). The percentage of participants who lost 5% or more of their initial weight was 18.8% in the control group, 38.2% in the group receiving remote support only, and 41.4% in the group receiving in-person support. The change in weight from baseline did not differ significantly between the two intervention groups. <br /><b>Conclusions:</b><br/> In two behavioral interventions, one delivered with in-person support and the other delivered remotely, without face-to-face contact between participants and weight-loss coaches, obese patients achieved and sustained clinically significant weight loss over a period of 24 months. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00783315 .).<br /><br /><small>N Engl J Med: 16 Nov 2011; epub ahead of print</small></div>
Appel LJ, Clark JM, Yeh HC, Wang NY, ... Louis TA, Brancati FL
N Engl J Med: 16 Nov 2011; epub ahead of print | PMID: 22085317
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<div><h4>Collaborative care for patients with depression and chronic illnesses.</h4><i>Katon WJ, Lin EH, Von Korff M, Ciechanowski P, ... McGregor M, McCulloch D</i><br /><b>Background:</b><br/>Patients with depression and poorly controlled diabetes, coronary heart disease, or both have an increased risk of adverse outcomes and high health care costs. We conducted a study to determine whether coordinated care management of multiple conditions improves disease control in these patients. Methods We conducted a single-blind, randomized, controlled trial in 14 primary care clinics in an integrated health care system in Washington State, involving 214 participants with poorly controlled diabetes, coronary heart disease, or both and coexisting depression. Patients were randomly assigned to the usual-care group or to the intervention group, in which a medically supervised nurse, working with each patient\'s primary care physician, provided guideline-based, collaborative care management, with the goal of controlling risk factors associated with multiple diseases. The primary outcome was based on simultaneous modeling of glycated hemoglobin, low-density lipoprotein (LDL) cholesterol, and systolic blood-pressure levels and Symptom Checklist-20 (SCL-20) depression outcomes at 12 months; this modeling allowed estimation of a single overall treatment effect. Results As compared with controls, patients in the intervention group had greater overall 12-month improvement across glycated hemoglobin levels (difference, 0.58%), LDL cholesterol levels (difference, 6.9 mg per deciliter [0.2 mmol per liter]), systolic blood pressure (difference, 5.1 mm Hg), and SCL-20 depression scores (difference, 0.40 points) (P<0.001). Patients in the intervention group also were more likely to have one or more adjustments of insulin (P=0.006), antihypertensive medications (P<0.001), and antidepressant medications (P<0.001), and they had better quality of life (P<0.001) and greater satisfaction with care for diabetes, coronary heart disease, or both (P<0.001) and with care for depression (P<0.001). <br /><b>Conclusions:</b><br/>As compared with usual care, an intervention involving nurses who provided guideline-based, patient-centered management of depression and chronic disease significantly improved control of medical disease and depression. (Funded by the National Institute of Mental Health; ClinicalTrials.gov number, NCT00468676 .).<br /><br /><small>N Engl J Med: 30 Dec 2010; 363:2611-20</small></div>
Katon WJ, Lin EH, Von Korff M, Ciechanowski P, ... McGregor M, McCulloch D
N Engl J Med: 30 Dec 2010; 363:2611-20 | PMID: 21190455
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<div><h4>Effects of CYP2C19 genotype on outcomes of clopidogrel treatment.</h4><i>Paré G, Mehta SR, Yusuf S, Anand SS, ... Fox KA, Eikelboom JW</i><br />BACKGROUND: It has been suggested that clopidogrel may be less effective in reducing the rate of cardiovascular events among persons who are carriers of loss-of-function CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its active metabolite. <br /><b>Methods:</b><br/>We genotyped patients from two large, randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events (the primary efficacy outcome) among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for three single-nucleotide polymorphisms (*2, *3, *17) that define the major CYP2C19 alleles. <br /><b>Results:</b><br/>Among 5059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype (P=0.12 for heterogeneity). The effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8.0% with clopidogrel vs. 11.6% with placebo; hazard ratio with clopidogrel, 0.69; 95% confidence interval [CI], 0.49 to 0.98; rate among noncarriers, 9.5% vs. 13.0%; hazard ratio, 0.72; 95% CI, 0.59 to 0.87). In contrast, gain-of-function carriers derived more benefit from clopidogrel treatment as compared with placebo than did noncarriers (rate of primary outcome among carriers, 7.7% vs. 13.0%; hazard ratio, 0.55; 95% CI, 0.42 to 0.73; rate among noncarriers, 10.0% vs. 12.2%; hazard ratio, 0.85; 95% CI, 0.68 to 1.05; P=0.02 for interaction). The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status. <br /><b>Conclusions:</b><br/>Among patients with acute coronary syndromes or atrial fibrillation, the effect of clopidogrel as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00249873.).<br /><br /><small>N Engl J Med: 28 Oct 2010; 363:1704-14</small></div>
Paré G, Mehta SR, Yusuf S, Anand SS, ... Fox KA, Eikelboom JW
N Engl J Med: 28 Oct 2010; 363:1704-14 | PMID: 20979470
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<div><h4>Low diagnostic yield of elective coronary angiography.</h4><i>Patel MR, Peterson ED, Dai D, Brennan JM, ... Brindis RG, Douglas PS</i><br />BACKGROUND: Guidelines for triaging patients for cardiac catheterization recommend a risk assessment and noninvasive testing. We determined patterns of noninvasive testing and the diagnostic yield of catheterization among patients with suspected coronary artery disease in a contemporary national sample. <br /><b>Methods:</b><br/>From January 2004 through April 2008, at 663 hospitals in the American College of Cardiology National Cardiovascular Data Registry, we identified patients without known coronary artery disease who were undergoing elective catheterization. The patients\' demographic characteristics, risk factors, and symptoms and the results of noninvasive testing were correlated with the presence of obstructive coronary artery disease, which was defined as stenosis of 50% or more of the diameter of the left main coronary artery or stenosis of 70% or more of the diameter of a major epicardial vessel. <br /><b>Results:</b><br/>A total of 398,978 patients were included in the study. The median age was 61 years; 52.7% of the patients were men, 26.0% had diabetes, and 69.6% had hypertension. Noninvasive testing was performed in 83.9% of the patients. At catheterization, 149,739 patients (37.6%) had obstructive coronary artery disease. No coronary artery disease (defined as <20% stenosis in all vessels) was reported in 39.2% of the patients. Independent predictors of obstructive coronary artery disease included male sex (odds ratio, 2.70; 95% confidence interval [CI], 2.64 to 2.76), older age (odds ratio per 5-year increment, 1.29; 95% CI, 1.28 to 1.30), presence of insulin-dependent diabetes (odds ratio, 2.14; 95% CI, 2.07 to 2.21), and presence of dyslipidemia (odds ratio, 1.62; 95% CI, 1.57 to 1.67). Patients with a positive result on a noninvasive test were moderately more likely to have obstructive coronary artery disease than those who did not undergo any testing (41.0% vs. 35.0%; P<0.001; adjusted odds ratio, 1.28; 95% CI, 1.19 to 1.37). <br /><b>Conclusions:</b><br/>In this study, slightly more than one third of patients without known disease who underwent elective cardiac catheterization had obstructive coronary artery disease. Better strategies for risk stratification are needed to inform decisions and to increase the diagnostic yield of cardiac catheterization in routine clinical practice.<br /><br /><small>N Engl J Med: 11 Mar 2010; 362:886-95</small></div>
Patel MR, Peterson ED, Dai D, Brennan JM, ... Brindis RG, Douglas PS
N Engl J Med: 11 Mar 2010; 362:886-95 | PMID: 20220183
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<div><h4>Ventricular Tachyarrhythmias after Cardiac Arrest in Public versus at Home.</h4><i>Weisfeldt ML, Everson-Stewart S, Sitlani C, Rea T, ... Morrison LJ, the Resuscitation Outcomes Consortium (ROC) Investigators</i><br /><b>Background:</b><br/>The incidence of ventricular fibrillation or pulseless ventricular tachycardia as the first recorded rhythm after out-of-hospital cardiac arrest has unexpectedly declined. The success of bystander-deployed automated external defibrillators (AEDs) in public settings suggests that this may be the more common initial rhythm when out-of-hospital cardiac arrest occurs in public. We conducted a study to determine whether the location of the arrest, the type of arrhythmia, and the probability of survival are associated. Methods Between 2005 and 2007, we conducted a prospective cohort study of out-of-hospital cardiac arrest in adults in 10 North American communities. We assessed the frequencies of ventricular fibrillation or pulseless ventricular tachycardia and of survival to hospital discharge for arrests at home as compared with arrests in public. Results Of 12,930 evaluated out-of-hospital cardiac arrests, 2042 occurred in public and 9564 at home. For cardiac arrests at home, the incidence of ventricular fibrillation or pulseless ventricular tachycardia was 25% when the arrest was witnessed by emergency-medical-services (EMS) personnel, 35% when it was witnessed by a bystander, and 36% when a bystander applied an AED. For cardiac arrests in public, the corresponding rates were 38%, 60%, and 79%. The adjusted odds ratio for initial ventricular fibrillation or pulseless ventricular tachycardia in public versus at home was 2.28 (95% confidence interval [CI], 1.96 to 2.66; P<0.001) for bystander-witnessed arrests and 4.48 (95% CI, 2.23 to 8.97; P<0.001) for arrests in which bystanders applied AEDs. The rate of survival to hospital discharge was 34% for arrests in public settings with AEDs applied by bystanders versus 12% for arrests at home (adjusted odds ratio, 2.49; 95% CI, 1.03 to 5.99; P=0.04). <br /><b>Conclusions:</b><br/>Regardless of whether out-of-hospital cardiac arrests are witnessed by EMS personnel or bystanders and whether AEDs are applied by bystanders, the proportion of arrests with initial ventricular fibrillation or pulseless ventricular tachycardia is much greater in public settings than at home. The incremental value of resuscitation strategies, such as the ready availability of an AED, may be related to the place where the arrest occurs. (Funded by the National Heart, Lung, and Blood Institute and others.).<br /><br /><small>N Engl J Med: 27 Jan 2011; 364:313-321</small></div>
Weisfeldt ML, Everson-Stewart S, Sitlani C, Rea T, ... Morrison LJ, the Resuscitation Outcomes Consortium (ROC) Investigators
N Engl J Med: 27 Jan 2011; 364:313-321 | PMID: 21268723
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<div><h4>Lenient versus Strict Rate Control in Patients with Atrial Fibrillation.</h4><i>Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, ... Van den Berg MP, the RACE II Investigators</i><br />BACKGROUND: Rate control is often the therapy of choice for atrial fibrillation. Guidelines recommend strict rate control, but this is not based on clinical evidence. We hypothesized that lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in patients with permanent atrial fibrillation. <br /><b>Methods:</b><br/>We randomly assigned 614 patients with permanent atrial fibrillation to undergo a lenient rate-control strategy (resting heart rate <110 beats per minute) or a strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. <br /><b>Results:</b><br/>The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of -2.0 percentage points (90% confidence interval, -7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P<0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. <br /><b>Conclusions:</b><br/>In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. (ClinicalTrials.gov number, NCT00392613.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 16 Mar 2010; epub ahead of print</small></div>
Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, ... Van den Berg MP, the RACE II Investigators
N Engl J Med: 16 Mar 2010; epub ahead of print | PMID: 20231232
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<div><h4>Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients.</h4><i>Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, ... Weitz JI, the ADOPT Trial Investigators</i><br /><b>Background:</b><br/> The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin. Methods In this double-blind, double-dummy, placebo-controlled trial, we randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated. Results A total of 6528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome - 2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P=0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P=0.04). <br /><b>Conclusions:</b><br/> In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00457002 .).<br /><br /><small>N Engl J Med: 14 Nov 2011; epub ahead of print</small></div>
Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, ... Weitz JI, the ADOPT Trial Investigators
N Engl J Med: 14 Nov 2011; epub ahead of print | PMID: 22077144
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<div><h4>Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation.</h4><i>Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, ... Valantine HA, the IMAGE Study Group</i><br />BACKGROUND: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. <br /><b>Methods:</b><br/>We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. <br /><b>Results:</b><br/>During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). <br /><b>Conclusions:</b><br/>Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 23 Apr 2010; epub ahead of print</small></div>
Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, ... Valantine HA, the IMAGE Study Group
N Engl J Med: 23 Apr 2010; epub ahead of print | PMID: 20413602
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<div><h4>Duration of Dual Antiplatelet Therapy after Implantation of Drug-Eluting Stents.</h4><i>Park SJ, Park DW, Kim YH, Kang SJ, ... Park HS, Lee K</i><br />BACKGROUND: The potential benefits and risks of the use of dual antiplatelet therapy beyond a 12-month period in patients receiving drug-eluting stents have not been clearly established. <br /><b>Methods:</b><br/>In two trials, we randomly assigned a total of 2701 patients who had received drug-eluting stents and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone. The primary end point was a composite of myocardial infarction or death from cardiac causes. Data from the two trials were merged for analysis. <br /><b>Results:</b><br/>The median duration of follow-up was 19.2 months. The cumulative risk of the primary outcome at 2 years was 1.8% with dual antiplatelet therapy, as compared with 1.2% with aspirin monotherapy (hazard ratio, 1.65; 95% confidence interval [CI], 0.80 to 3.36; P=0.17). The individual risks of myocardial infarction, stroke, stent thrombosis, need for repeat revascularization, major bleeding, and death from any cause did not differ significantly between the two groups. However, in the dual-therapy group as compared with the aspirin-alone group, there was a nonsignificant increase in the composite risk of myocardial infarction, stroke, or death from any cause (hazard ratio, 1.73; 95% CI, 0.99 to 3.00; P=0.051) and in the composite risk of myocardial infarction, stroke, or death from cardiac causes (hazard ratio, 1.84; 95% CI, 0.99 to 3.45; P=0.06). <br /><b>Conclusions:</b><br/>The use of dual antiplatelet therapy for a period longer than 12 months in patients who had received drug-eluting stents was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infarction or death from cardiac causes. These findings should be confirmed or refuted through larger, randomized clinical trials with longer-term follow-up. (ClinicalTrials.gov numbers, NCT00484926 and NCT00590174.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 16 Mar 2010; epub ahead of print</small></div>
Park SJ, Park DW, Kim YH, Kang SJ, ... Park HS, Lee K
N Engl J Med: 16 Mar 2010; epub ahead of print | PMID: 20231231
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<div><h4>Ferric carboxymaltose in patients with heart failure and iron deficiency.</h4><i>Anker SD, Comin Colet J, Filippatos G, Willenheimer R, ... Ponikowski P, </i><br />BACKGROUND: Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. <br /><b>Methods:</b><br/>We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. <br /><b>Results:</b><br/>Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. <br /><b>Conclusions:</b><br/>Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780).<br /><br /><small>N Engl J Med: 18 Dec 2009; 361:2436-48</small></div>
Anker SD, Comin Colet J, Filippatos G, Willenheimer R, ... Ponikowski P,
N Engl J Med: 18 Dec 2009; 361:2436-48 | PMID: 19920054
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<div><h4>Intravenous platelet blockade with cangrelor during PCI.</h4><i>Bhatt DL, Lincoff AM, Gibson CM, Stone GW, ... Harrington RA, </i><br />BACKGROUND: Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI). <br /><b>Methods:</b><br/>In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point. <br /><b>Results:</b><br/>The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas. <br /><b>Conclusions:</b><br/>The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)<br /><br /><small>N Engl J Med: 16 Dec 2009; 361:2330-41</small></div>
Bhatt DL, Lincoff AM, Gibson CM, Stone GW, ... Harrington RA,
N Engl J Med: 16 Dec 2009; 361:2330-41 | PMID: 19915222
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<div><h4>Comparison of Zotarolimus-Eluting and Everolimus-Eluting Coronary Stents.</h4><i>Serruys PW, Silber S, Garg S, van Geuns RJ, ... van Leeuwen F, Windecker S</i><br />BACKGROUND: New-generation coronary stents that release zotarolimus or everolimus have been shown to reduce the risk of restenosis. However, it is unclear whether there are differences in efficacy and safety between the two types of stents on the basis of prospectively adjudicated end points endorsed by the Food and Drug Administration. <br /><b>Methods:</b><br/>In this multicenter, noninferiority trial with minimal exclusion criteria, we randomly assigned 2292 patients to undergo treatment with coronary stents releasing either zotarolimus or everolimus. Twenty percent of patients were randomly selected for repeat angiography at 13 months. The primary end point was target-lesion failure, defined as a composite of death from cardiac causes, any myocardial infarction (not clearly attributable to a nontarget vessel), or clinically indicated target-lesion revascularization within 12 months. The secondary angiographic end point was the extent of in-stent stenosis at 13 months. <br /><b>Results:</b><br/>At least one off-label criterion for stent placement was present in 66% of patients. The zotarolimus-eluting stent was noninferior to the everolimus-eluting stent with respect to the primary end point, which occurred in 8.2% and 8.3% of patients, respectively (P<0.001 for noninferiority). There were no significant between-group differences in the rate of death from cardiac causes, any myocardial infarction, or revascularization. The rate of stent thrombosis was 2.3% in the zotarolimus-stent group and 1.5% in the everolimus-stent group (P=0.17). The zotarolimus-eluting stent was also noninferior regarding the degree (+/-SD) of in-stent stenosis (21.65+/-14.42% for zotarolimus vs. 19.76+/-14.64% for everolimus, P=0.04 for noninferiority). In-stent late lumen loss was 0.27+/-0.43 mm in the zotarolimus-stent group versus 0.19+/-0.40 mm in the everolimus-stent group (P=0.08). There were no significant between-group differences in the rate of adverse events. <br /><b>Conclusions:</b><br/>At 13 months, the new-generation zotarolimus-eluting stent was found to be noninferior to the everolimus-eluting stent in a population of patients who had minimal exclusion criteria. (ClinicalTrials.gov number, NCT00617084.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 17 Jun 2010; epub ahead of print</small></div>
Serruys PW, Silber S, Garg S, van Geuns RJ, ... van Leeuwen F, Windecker S
N Engl J Med: 17 Jun 2010; epub ahead of print | PMID: 20554978
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<div><h4>CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea.</h4><i>McEvoy RD, Antic NA, Heeley E, Luo Y, ... Anderson CS, SAVE Investigators and Coordinators</i><br /><b>Background:</b><br/>Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. Methods After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. Results Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. <br /><b>Conclusions:</b><br/>Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).<br /><br /><small>N Engl J Med: 28 Aug 2016; epub ahead of print</small></div>
McEvoy RD, Antic NA, Heeley E, Luo Y, ... Anderson CS, SAVE Investigators and Coordinators
N Engl J Med: 28 Aug 2016; epub ahead of print | PMID: 27571048
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<div><h4>Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia.</h4><i>Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, ... Baxter JD, Angelin B</i><br />BACKGROUND: Dyslipidemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Thyroid hormone lowers levels of serum low-density lipoprotein (LDL) cholesterol and has other potentially favorable actions on lipoprotein metabolism. Consequently, thyromimetic drugs hold promise as lipid-lowering agents if adverse effects can be avoided. <br /><b>Methods:</b><br/>We performed a randomized, placebo-controlled, double-blind, multicenter trial to assess the safety and efficacy of the thyromimetic compound eprotirome (KB2115) in lowering the level of serum LDL cholesterol in patients with hypercholesterolemia who were already receiving simvastatin or atorvastatin. In addition to statin treatment, patients received either eprotirome (at a dose of 25, 50, or 100 microg per day) or placebo. Secondary outcomes were changes in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Patients were monitored for potential adverse thyromimetic effects on the heart, bone, and pituitary. <br /><b>Results:</b><br/>The addition of placebo or eprotirome at a dose of 25, 50, or 100 microg daily to statin treatment for 12 weeks reduced the mean level of serum LDL cholesterol from 141 mg per deciliter (3.6 mmol per liter) to 127, 113, 99, and 94 mg per deciliter (3.3, 2.9, 2.6, and 2.4 mmol per liter), respectively, (mean reduction from baseline, 7%, 22%, 28%, and 32%). Similar reductions were seen in levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein. Eprotirome therapy was not associated with adverse effects on the heart or bone. No change in levels of serum thyrotropin or triiodothyronine was detected, although the thyroxine level decreased in patients receiving eprotirome. <br /><b>Conclusions:</b><br/>In this 12-week trial, the thyroid hormone analogue eprotirome was associated with decreases in levels of atherogenic lipoproteins in patients receiving treatment with statins. (ClinicalTrials.gov number, NCT00593047.)<br /><br /><small>N Engl J Med: 11 Mar 2010; 362:906-16</small></div>
Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, ... Baxter JD, Angelin B
N Engl J Med: 11 Mar 2010; 362:906-16 | PMID: 20220185
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<div><h4>Platelet inhibition with cangrelor in patients undergoing PCI.</h4><i>Harrington RA, Stone GW, McNulty S, White HD, ... Skerjanec S, Bhatt DL</i><br />BACKGROUND: Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition. <br /><b>Methods:</b><br/>We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. <br /><b>Results:</b><br/>We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14). <br /><b>Conclusions:</b><br/>Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.)<br /><br /><small>N Engl J Med: 16 Dec 2009; 361:2318-29</small></div>
Harrington RA, Stone GW, McNulty S, White HD, ... Skerjanec S, Bhatt DL
N Engl J Med: 16 Dec 2009; 361:2318-29 | PMID: 19915221
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<div><h4>Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Disease.</h4><i>Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL</i><br /><b>Background:</b><br/>Results of trials and registry studies have shown lower long-term mortality after coronary-artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI) among patients with multivessel disease. These previous analyses did not evaluate PCI with second-generation drug-eluting stents. Methods In an observational registry study, we compared the outcomes in patients with multivessel disease who underwent CABG with the outcomes in those who underwent PCI with the use of everolimus-eluting stents. The primary outcome was all-cause mortality. Secondary outcomes were the rates of myocardial infarction, stroke, and repeat revascularization. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Results Among 34,819 eligible patients, 9223 patients who underwent PCI with everolimus-eluting stents and 9223 who underwent CABG had similar propensity scores and were included in the analyses. At a mean follow-up of 2.9 years, PCI with everolimus-eluting stents, as compared with CABG, was associated with a similar risk of death (3.1% per year and 2.9% per year, respectively; hazard ratio, 1.04; 95% confidence interval [CI], 0.93 to 1.17; P=0.50), higher risks of myocardial infarction (1.9% per year vs. 1.1% per year; hazard ratio, 1.51; 95% CI, 1.29 to 1.77; P<0.001) and repeat revascularization (7.2% per year vs. 3.1% per year; hazard ratio, 2.35; 95% CI, 2.14 to 2.58; P<0.001), and a lower risk of stroke (0.7% per year vs. 1.0% per year; hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). The higher risk of myocardial infarction with PCI than with CABG was not significant among patients with complete revascularization but was significant among those with incomplete revascularization (P=0.02 for interaction). <br /><b>Conclusions:</b><br/>In a contemporary clinical-practice registry study, the risk of death associated with PCI with everolimus-eluting stents was similar to that associated with CABG. PCI was associated with a higher risk of myocardial infarction (among patients with incomplete revascularization) and repeat revascularization but a lower risk of stroke. (Funded by Abbott Vascular.).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Bangalore S, Guo Y, Samadashvili Z, Blecker S, Xu J, Hannan EL
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25775087
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<div><h4>Randomized Trial of Primary PCI with or without Routine Manual Thrombectomy.</h4><i>Jolly SS, Cairns JA, Yusuf S, Meeks B, ... Džavík V, TOTAL Investigators</i><br /><b>Background:</b><br/>During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results. Methods We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days. Results The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P=0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P=0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P=0.02). <br /><b>Conclusions:</b><br/>In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days. (Funded by Medtronic and the Canadian Institutes of Health Research; TOTAL ClinicalTrials.gov number, NCT01149044 .).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Jolly SS, Cairns JA, Yusuf S, Meeks B, ... Džavík V, TOTAL Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25775387
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<div><h4>Trial of Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease.</h4><i>Park SJ, Ahn JM, Kim YH, Park DW, ... Ong TK, BEST Trial Investigators</i><br /><b>Background:</b><br/>Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents. Methods We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups. Results After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval [CI], -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG. <br /><b>Conclusions:</b><br/>Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828 .).<br /><br /><small>N Engl J Med: 15 Mar 2015; epub ahead of print</small></div>
Park SJ, Ahn JM, Kim YH, Park DW, ... Ong TK, BEST Trial Investigators
N Engl J Med: 15 Mar 2015; epub ahead of print | PMID: 25774645
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<div><h4>Perilipin deficiency and autosomal dominant partial lipodystrophy.</h4><i>Gandotra S, Le Dour C, Bottomley W, Cervera P, ... Savage DB, Vigouroux C</i><br />Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.<br /><br /><small>N Engl J Med: 24 Feb 2011; 364:740-8</small></div>
Gandotra S, Le Dour C, Bottomley W, Cervera P, ... Savage DB, Vigouroux C
N Engl J Med: 24 Feb 2011; 364:740-8 | PMID: 21345103
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<div><h4>Genetic Basis for In Vivo Daptomycin Resistance in Enterococci.</h4><i>Arias CA, Panesso D, McGrath DM, Qin X, ... Murray BE, Weinstock GM</i><br /><b>Background:</b><br/>Daptomycin is a lipopeptide with bactericidal activity that acts on the cell membrane of enterococci and is often used off-label to treat patients infected with vancomycin-resistant enterococci. However, the emergence of resistance to daptomycin during therapy threatens its usefulness. Methods We performed whole-genome sequencing and characterization of the cell envelope of a clinical pair of vancomycin-resistant Enterococcus faecalis isolates from the blood of a patient with fatal bacteremia; one isolate (S613) was from blood drawn before treatment and the other isolate (R712) was from blood drawn after treatment with daptomycin. The minimal inhibitory concentrations (MICs) of these two isolates were 1 and 12 μg per milliliter, respectively. Gene replacements were made to exchange the alleles found in isolate S613 with those in isolate R712. Results Isolate R712 had in-frame deletions in three genes. Two genes encoded putative enzymes involved in phospholipid metabolism, GdpD (which denotes glycerophosphoryl diester phosphodiesterase) and Cls (which denotes cardiolipin synthetase), and one gene encoded a putative membrane protein, LiaF (which denotes lipid II cycle-interfering antibiotics protein but whose exact function is not known). LiaF is predicted to be a member of a three-component regulatory system (LiaFSR) involved in the stress-sensing response of the cell envelope to antibiotics. Replacement of the liaF allele of isolate S613 with the liaF allele from isolate R712 quadrupled the MIC of daptomycin, whereas replacement of the gdpD allele had no effect on MIC. Replacement of both the liaF and gdpD alleles of isolate S613 with the liaF and gdpD alleles of isolate R712 raised the daptomycin MIC for isolate S613 to 12 μg per milliliter. As compared with isolate S613, isolate R712 - the daptomycin-resistant isolate - had changes in the structure of the cell envelope and alterations in membrane permeability and membrane potential. <br /><b>Conclusions:</b><br/>Mutations in genes encoding LiaF and a GdpD-family protein were necessary and sufficient for the development of resistance to daptomycin during the treatment of vancomycin-resistant enterococci. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health.).<br /><br /><small>N Engl J Med: 08 Sep 2011; 365:892-900</small></div>
Arias CA, Panesso D, McGrath DM, Qin X, ... Murray BE, Weinstock GM
N Engl J Med: 08 Sep 2011; 365:892-900 | PMID: 21899450
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<div><h4>Percent emphysema, airflow obstruction, and impaired left ventricular filling.</h4><i>Barr RG, Bluemke DA, Ahmed FS, Carr JJ, ... Smith LJ, Watson KE</i><br />BACKGROUND: Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease. <br /><b>Methods:</b><br/>We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects. <br /><b>Results:</b><br/>Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval [CI], -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction. <br /><b>Conclusions:</b><br/>In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.<br /><br /><small>N Engl J Med: 21 Jan 2010; 362:217-27</small></div>
Barr RG, Bluemke DA, Ahmed FS, Carr JJ, ... Smith LJ, Watson KE
N Engl J Med: 21 Jan 2010; 362:217-27 | PMID: 20089972
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<div><h4>Population trends in the incidence and outcomes of acute myocardial infarction.</h4><i>Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS</i><br />BACKGROUND: Few studies have characterized recent population trends in the incidence and outcomes of myocardial infarction. <br /><b>Methods:</b><br/>We identified patients 30 years of age or older in a large, diverse, community-based population who were hospitalized for incident myocardial infarction between 1999 and 2008. Age- and sex-adjusted incidence rates were calculated for myocardial infarction overall and separately for ST-segment elevation and non-ST-segment elevation myocardial infarction. Patient characteristics, outpatient medications, and cardiac biomarker levels during hospitalization were identified from health plan databases, and 30-day mortality was ascertained from administrative databases, state death data, and Social Security Administration files. <br /><b>Results:</b><br/>We identified 46,086 hospitalizations for myocardial infarctions during 18,691,131 person-years of follow-up from 1999 to 2008. The age- and sex-adjusted incidence of myocardial infarction increased from 274 cases per 100,000 person-years in 1999 to 287 cases per 100,000 person-years in 2000, and it decreased each year thereafter, to 208 cases per 100,000 person-years in 2008, representing a 24% relative decrease over the study period. The age- and sex-adjusted incidence of ST-segment elevation myocardial infarction decreased throughout the study period (from 133 cases per 100,000 person-years in 1999 to 50 cases per 100,000 person-years in 2008, P<0.001 for linear trend). Thirty-day mortality was significantly lower in 2008 than in 1999 (adjusted odds ratio, 0.76; 95% confidence interval, 0.65 to 0.89). <br /><b>Conclusions:</b><br/>Within a large community-based population, the incidence of myocardial infarction decreased significantly after 2000, and the incidence of ST-segment elevation myocardial infarction decreased markedly after 1999. Reductions in short-term case fatality rates for myocardial infarction appear to be driven, in part, by a decrease in the incidence of ST-segment elevation myocardial infarction and a lower rate of death after non-ST-segment elevation myocardial infarction. Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 18 Jun 2010; 362:2155-65</small></div>
Yeh RW, Sidney S, Chandra M, Sorel M, Selby JV, Go AS
N Engl J Med: 18 Jun 2010; 362:2155-65 | PMID: 20558366
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<div><h4>Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery.</h4><i>Gillinov AM, Bagiella E, Moskowitz AJ, Raiten JM, ... Mack MJ, CTSN</i><br /><b>Background:</b><br/>Atrial fibrillation after cardiac surgery is associated with increased rates of death, complications, and hospitalizations. In patients with postoperative atrial fibrillation who are in stable condition, the best initial treatment strategy - heart-rate control or rhythm control - remains controversial. Methods Patients with new-onset postoperative atrial fibrillation were randomly assigned to undergo either rate control or rhythm control. The primary end point was the total number of days of hospitalization within 60 days after randomization, as assessed by the Wilcoxon rank-sum test. Results Postoperative atrial fibrillation occurred in 695 of the 2109 patients (33.0%) who were enrolled preoperatively; of these patients, 523 underwent randomization. The total numbers of hospital days in the rate-control group and the rhythm-control group were similar (median, 5.1 days and 5.0 days, respectively; P=0.76). There were no significant between-group differences in the rates of death (P=0.64) or overall serious adverse events (24.8 per 100 patient-months in the rate-control group and 26.4 per 100 patient-months in the rhythm-control group, P=0.61), including thromboembolic and bleeding events. About 25% of the patients in each group deviated from the assigned therapy, mainly because of drug ineffectiveness (in the rate-control group) or amiodarone side effects or adverse drug reactions (in the rhythm-control group). At 60 days, 93.8% of the patients in the rate-control group and 97.9% of those in the rhythm-control group had had a stable heart rhythm without atrial fibrillation for the previous 30 days (P=0.02), and 84.2% and 86.9%, respectively, had been free from atrial fibrillation from discharge to 60 days (P=0.41). <br /><b>Conclusions:</b><br/>Strategies for rate control and rhythm control to treat postoperative atrial fibrillation were associated with equal numbers of days of hospitalization, similar complication rates, and similarly low rates of persistent atrial fibrillation 60 days after onset. Neither treatment strategy showed a net clinical advantage over the other. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02132767 .).<br /><br /><small>N Engl J Med: 03 Apr 2016; epub ahead of print</small></div>
Gillinov AM, Bagiella E, Moskowitz AJ, Raiten JM, ... Mack MJ, CTSN
N Engl J Med: 03 Apr 2016; epub ahead of print | PMID: 27043047
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<div><h4>Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.</h4><i>Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, ... Buse JB, LEADER Steering Committee on behalf of the LEADER Trial Investigators</i><br /><b>Background:</b><br/>The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. <br /><b>Conclusions:</b><br/>In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .).<br /><br /><small>N Engl J Med: 12 Jun 2016; epub ahead of print</small></div>
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, ... Buse JB, LEADER Steering Committee on behalf of the LEADER Trial Investigators
N Engl J Med: 12 Jun 2016; epub ahead of print | PMID: 27295427
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<div><h4>Genetic variants associated with Lp(a) lipoprotein level and coronary disease.</h4><i>Clarke R, Peden JF, Hopewell JC, Kyriakou T, ... Farrall M, </i><br />BACKGROUND: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. <br /><b>Methods:</b><br/>We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. <br /><b>Results:</b><br/>Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. <br /><b>Conclusions:</b><br/>We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.<br /><br /><small>N Engl J Med: 24 Dec 2009; 361:2518-28</small></div>
Clarke R, Peden JF, Hopewell JC, Kyriakou T, ... Farrall M,
N Engl J Med: 24 Dec 2009; 361:2518-28 | PMID: 20032323
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<div><h4>One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke.</h4><i>Amarenco P, Lavallée PC, Labreuche J, Albers GW, ... Wong LK, TIAregistry.org Investigators</i><br /><b>Background:</b><br/>Previous studies conducted between 1997 and 2003 estimated that the risk of stroke or an acute coronary syndrome was 12 to 20% during the first 3 months after a transient ischemic attack (TIA) or minor stroke. The TIAregistry.org project was designed to describe the contemporary profile, etiologic factors, and outcomes in patients with a TIA or minor ischemic stroke who receive care in health systems that now offer urgent evaluation by stroke specialists. Methods We recruited patients who had had a TIA or minor stroke within the previous 7 days. Sites were selected if they had systems dedicated to urgent evaluation of patients with TIA. We estimated the 1-year risk of stroke and of the composite outcome of stroke, an acute coronary syndrome, or death from cardiovascular causes. We also examined the association of the ABCD(2) score for the risk of stroke (range, 0 [lowest risk] to 7 [highest risk]), findings on brain imaging, and cause of TIA or minor stroke with the risk of recurrent stroke over a period of 1 year. Results From 2009 through 2011, we enrolled 4789 patients at 61 sites in 21 countries. A total of 78.4% of the patients were evaluated by stroke specialists within 24 hours after symptom onset. A total of 33.4% of the patients had an acute brain infarction, 23.2% had at least one extracranial or intracranial stenosis of 50% or more, and 10.4% had atrial fibrillation. The Kaplan-Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2% (95% confidence interval, 5.5 to 7.0). Kaplan-Meier estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. In multivariable analyses, multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD(2) score of 6 or 7 were each associated with more than a doubling of the risk of stroke. <br /><b>Conclusions:</b><br/>We observed a lower risk of cardiovascular events after TIA than previously reported. The ABCD(2) score, findings on brain imaging, and status with respect to large-artery atherosclerosis helped stratify the risk of recurrent stroke within 1 year after a TIA or minor stroke. (Funded by Sanofi and Bristol-Myers Squibb.).<br /><br /><small>N Engl J Med: 19 Apr 2016; 374:1533-1542</small></div>
Amarenco P, Lavallée PC, Labreuche J, Albers GW, ... Wong LK, TIAregistry.org Investigators
N Engl J Med: 19 Apr 2016; 374:1533-1542 | PMID: 27096581
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<div><h4>Dabigatran versus warfarin in the treatment of acute venous thromboembolism.</h4><i>Schulman S, Kearon C, Kakkar AK, Mismetti P, ... Goldhaber SZ, </i><br />BACKGROUND: The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. <br /><b>Methods:</b><br/>In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. <br /><b>Results:</b><br/>A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). <br /><b>Conclusions:</b><br/>For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.)<br /><br /><small>N Engl J Med: 16 Dec 2009; 361:2342-52</small></div>
Schulman S, Kearon C, Kakkar AK, Mismetti P, ... Goldhaber SZ,
N Engl J Med: 16 Dec 2009; 361:2342-52 | PMID: 19966341
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<div><h4>Chronic hypertension in pregnancy.</h4><i></i><br />Chronic Hypertension in Pregnancy Clinical Practice, N Engl J Med 2011;365:439-446. In Table 2 (page 444), some of the information listed under "Canadian (2008)" was incorrect. In the "Blood-pressure levels for treatment and goals" row, the Canadian information should have read, "Treat if blood pressure is >159 mm Hg systolic or >109 mm Hg diastolic to lower risk" and "Suggested target <156 mm Hg systolic and <106 mm Hg diastolic, but in patients with major cardiovascular risk factors, <140 mm Hg systolic and <90 mm Hg diastolic." In the "Medications" row, the entry beginning "First-line" should have read, "Most commonly used, methyldopa and labetalol; acceptable use, other beta-blockers and calcium-channel blockers." Also, under "Australasian (2000)," the suggested target given in the "Blood-pressure levels for treatment and goals" row should have been 120-140 mm Hg systolic, rather than 110-140 mm Hg systolic. The article is correct at NEJM.org.<br /><br /><small>N Engl J Med: 27 Oct 2011; 365:1650</small></div>
N Engl J Med: 27 Oct 2011; 365:1650 | PMID: 22030003
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<div><h4>Revascularization versus medical therapy for renal-artery stenosis.</h4><i> , Wheatley K, Ives N, Gray R, ... Nicholson A, Scoble J</i><br />BACKGROUND: Percutaneous revascularization of the renal arteries improves patency in atherosclerotic renovascular disease, yet evidence of a clinical benefit is limited. <br /><b>Methods:</b><br/>In a randomized, unblinded trial, we assigned 806 patients with atherosclerotic renovascular disease either to undergo revascularization in addition to receiving medical therapy or to receive medical therapy alone. The primary outcome was renal function, as measured by the reciprocal of the serum creatinine level (a measure that has a linear relationship with creatinine clearance). Secondary outcomes were blood pressure, the time to renal and major cardiovascular events, and mortality. The median follow-up was 34 months. <br /><b>Results:</b><br/>During a 5-year period, the rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was -0.07x10(-3) liters per micromole per year in the revascularization group, as compared with -0.13x10(-3) liters per micromole per year in the medical-therapy group, a difference favoring revascularization of 0.06x10(-3) liters per micromole per year (95% confidence interval [CI], -0.002 to 0.13; P=0.06). Over the same time, the mean serum creatinine level was 1.6 micromol per liter (95% CI, -8.4 to 5.2 [0.02 mg per deciliter; 95% CI, -0.10 to 0.06]) lower in the revascularization group than in the medical-therapy group. There was no significant between-group difference in systolic blood pressure; the decrease in diastolic blood pressure was smaller in the revascularization group than in the medical-therapy group. The two study groups had similar rates of renal events (hazard ratio in the revascularization group, 0.97; 95% CI, 0.67 to 1.40; P=0.88), major cardiovascular events (hazard ratio, 0.94; 95% CI, 0.75 to 1.19; P=0.61), and death (hazard ratio, 0.90; 95% CI, 0.69 to 1.18; P=0.46). Serious complications associated with revascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs. <br /><b>Conclusions:</b><br/>We found substantial risks but no evidence of a worthwhile clinical benefit from revascularization in patients with atherosclerotic renovascular disease. (Current Controlled Trials number, ISRCTN59586944.)<br /><br /><small>N Engl J Med: 12 Nov 2009; 361:1953-62</small></div>
, Wheatley K, Ives N, Gray R, ... Nicholson A, Scoble J
N Engl J Med: 12 Nov 2009; 361:1953-62 | PMID: 19907042
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<div><h4>Mutations in the Lysosomal Enzyme-Targeting Pathway and Persistent Stuttering.</h4><i>Kang C, Riazuddin S, Mundorff J, Krasnewich D, ... Mullikin JC, Drayna D</i><br />BACKGROUND: Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12. <br /><b>Methods:</b><br/>We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America. <br /><b>Results:</b><br/>We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms. <br /><b>Conclusions:</b><br/>Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism. Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 11 Feb 2010; epub ahead of print</small></div>
Kang C, Riazuddin S, Mundorff J, Krasnewich D, ... Mullikin JC, Drayna D
N Engl J Med: 11 Feb 2010; epub ahead of print | PMID: 20147709
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<div><h4>A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis.</h4><i>Kappos L, Radue EW, O\'Connor P, Polman C, ... Burtin P, the FREEDOMS Study Group</i><br />BACKGROUND: Oral fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis. <br /><b>Methods:</b><br/>In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing-remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point). <br /><b>Results:</b><br/>A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T(2) -weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension. <br /><b>Conclusions:</b><br/>As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978.) Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 21 Jan 2010; epub ahead of print</small></div>
Kappos L, Radue EW, O'Connor P, Polman C, ... Burtin P, the FREEDOMS Study Group
N Engl J Med: 21 Jan 2010; epub ahead of print | PMID: 20089952
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<div><h4>Weight Loss and Health Status 3 Years after Bariatric Surgery in Adolescents.</h4><i>Inge TH, Courcoulas AP, Jenkins TM, Michalsky MP, ... Buncher CR, Teen-LABS Consortium</i><br /><b>Background:</b><br/>Bariatric surgery is increasingly considered for the treatment of adolescents with severe obesity, but few prospective adolescent-specific studies examining the efficacy and safety of weight-loss surgery are available to support clinical decision making. Methods We prospectively enrolled 242 adolescents undergoing weight-loss surgery at five U.S. centers. Patients undergoing Roux-en-Y gastric bypass (161 participants) or sleeve gastrectomy (67) were included in the analysis. Changes in body weight, coexisting conditions, cardiometabolic risk factors, and weight-related quality of life and postoperative complications were evaluated through 3 years after the procedure. Results The mean (±SD) baseline age of the participants was 17±1.6 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 53; 75% of the participants were female, and 72% were white. At 3 years after the procedure, the mean weight had decreased by 27% (95% confidence interval [CI], 25 to 29) in the total cohort, by 28% (95% CI, 25 to 30) among participants who underwent gastric bypass, and by 26% (95% CI, 22 to 30) among those who underwent sleeve gastrectomy. By 3 years after the procedure, remission of type 2 diabetes occurred in 95% (95% CI, 85 to 100) of participants who had had the condition at baseline, remission of abnormal kidney function occurred in 86% (95% CI, 72 to 100), remission of prediabetes in 76% (95% CI, 56 to 97), remission of elevated blood pressure in 74% (95% CI, 64 to 84), and remission of dyslipidemia in 66% (95% CI, 57 to 74). Weight-related quality of life also improved significantly. However, at 3 years after the bariatric procedure, hypoferritinemia was found in 57% (95% CI, 50 to 65) of the participants, and 13% (95% CI, 9 to 18) of the participants had undergone one or more additional intraabdominal procedures. <br /><b>Conclusions:</b><br/>In this multicenter, prospective study of bariatric surgery in adolescents, we found significant improvements in weight, cardiometabolic health, and weight-related quality of life at 3 years after the procedure. Risks associated with surgery included specific micronutrient deficiencies and the need for additional abdominal procedures. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; Teen-LABS ClinicalTrials.gov number, NCT00474318 .).<br /><br /><small>N Engl J Med: 05 Nov 2015; epub ahead of print</small></div>
Inge TH, Courcoulas AP, Jenkins TM, Michalsky MP, ... Buncher CR, Teen-LABS Consortium
N Engl J Med: 05 Nov 2015; epub ahead of print | PMID: 26544725
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<div><h4>Clopidogrel with or without Omeprazole in Coronary Artery Disease.</h4><i>Bhatt DL, Cryer BL, Contant CF, Cohen M, ... Murphy SA, Cannon CP</i><br /><b>Background:</b><br/>Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. Methods We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. Results We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P=0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P=0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. <br /><b>Conclusions:</b><br/>Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).<br /><br /><small>N Engl J Med: 07 Oct 2010; epub ahead of print</small></div>
Bhatt DL, Cryer BL, Contant CF, Cohen M, ... Murphy SA, Cannon CP
N Engl J Med: 07 Oct 2010; epub ahead of print | PMID: 20925534
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<div><h4>Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure.</h4><i>Massie BM, O\'Connor CM, Metra M, Ponikowski P, ... Dittrich HC, PROTECT Investigators and Committees</i><br />BACKGROUND: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1-receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. <br /><b>Methods:</b><br/>We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient\'s clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. <br /><b>Results:</b><br/>Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. <br /><b>Conclusions:</b><br/>Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.).<br /><br /><small>N Engl J Med: 07 Oct 2010; 363:1419-28</small></div>
Massie BM, O'Connor CM, Metra M, Ponikowski P, ... Dittrich HC, PROTECT Investigators and Committees
N Engl J Med: 07 Oct 2010; 363:1419-28 | PMID: 20925544
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<div><h4>n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction.</h4><i>Kromhout D, Giltay EJ, Geleijnse JM</i><br /><b>Background:</b><br/>Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n−3 fatty acids against cardiovascular diseases. We examined the effect of the marine n−3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction. Methods In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA–DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA–DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models. Results The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA–DHA nor ALA reduced this primary end point (hazard ratio with EPA–DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA–DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups. <br /><b>Conclusions:</b><br/>Low-dose supplementation with EPA–DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy. (Funded by the Netherlands Heart Foundation and others; ClinicalTrials.gov number, NCT00127452.).<br /><br /><small>N Engl J Med: 08 Oct 2010; epub ahead of print</small></div>
Kromhout D, Giltay EJ, Geleijnse JM
N Engl J Med: 08 Oct 2010; epub ahead of print | PMID: 20929341
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<div><h4>Projected Effect of Dietary Salt Reductions on Future Cardiovascular Disease.</h4><i>Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, ... Pletcher MJ, Goldman L</i><br />BACKGROUND: The U.S. diet is high in salt, with the majority coming from processed foods. Reducing dietary salt is a potentially important target for the improvement of public health. <br /><b>Methods:</b><br/>We used the Coronary Heart Disease (CHD) Policy Model to quantify the benefits of potentially achievable, population-wide reductions in dietary salt of up to 3 g per day (1200 mg of sodium per day). We estimated the rates and costs of cardiovascular disease in subgroups defined by age, sex, and race; compared the effects of salt reduction with those of other interventions intended to reduce the risk of cardiovascular disease; and determined the cost-effectiveness of salt reduction as compared with the treatment of hypertension with medications. <br /><b>Results:</b><br/>Reducing dietary salt by 3 g per day is projected to reduce the annual number of new cases of CHD by 60,000 to 120,000, stroke by 32,000 to 66,000, and myocardial infarction by 54,000 to 99,000 and to reduce the annual number of deaths from any cause by 44,000 to 92,000. All segments of the population would benefit, with blacks benefiting proportionately more, women benefiting particularly from stroke reduction, older adults from reductions in CHD events, and younger adults from lower mortality rates. The cardiovascular benefits of reduced salt intake are on par with the benefits of population-wide reductions in tobacco use, obesity, and cholesterol levels. A regulatory intervention designed to achieve a reduction in salt intake of 3 g per day would save 194,000 to 392,000 quality-adjusted life-years and $10 billion to $24 billion in health care costs annually. Such an intervention would be cost-saving even if only a modest reduction of 1 g per day were achieved gradually between 2010 and 2019 and would be more cost-effective than using medications to lower blood pressure in all persons with hypertension. <br /><b>Conclusions:</b><br/>Modest reductions in dietary salt could substantially reduce cardiovascular events and medical costs and should be a public health target. Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 21 Jan 2010; epub ahead of print</small></div>
Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, ... Pletcher MJ, Goldman L
N Engl J Med: 21 Jan 2010; epub ahead of print | PMID: 20089957
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<div><h4>Nationwide public-access defibrillation in Japan.</h4><i>Kitamura T, Iwami T, Kawamura T, Nagao K, ... Hiraide A, Implementation Working Group for the All-Japan Utstein Registry of the Fire and Disaster Management Agency</i><br />BACKGROUND: It is unclear whether dissemination of automated external defibrillators (AEDs) in public places can improve the rate of survival among patients who have had an out-of-hospital cardiac arrest. <br /><b>Methods:</b><br/>From January 1, 2005, through December 31, 2007, we conducted a prospective, population-based, observational study involving consecutive patients across Japan who had an out-of-hospital cardiac arrest and in whom resuscitation was attempted by emergency responders. We evaluated the effect of nationwide dissemination of public-access AEDs on the rate of survival after an out-of-hospital cardiac arrest. The primary outcome measure was the 1-month rate of survival with minimal neurologic impairment. A multivariate logistic-regression analysis was performed to assess factors associated with a good neurologic outcome. <br /><b>Results:</b><br/>A total of 312,319 adults who had an out-of-hospital cardiac arrest were included in the study; 12,631 of these patients had ventricular fibrillation and had an arrest that was of cardiac origin and that was witnessed by bystanders. In 462 of these patients (3.7%), shocks were administered by laypersons with the use of public-access AEDs, and the proportion increased, from 1.2% to 6.2%, as the number of public-access AEDs increased (P<0.001 for trend). Among all patients who had a bystander-witnessed arrest of cardiac origin and who had ventricular fibrillation, 14.4% were alive at 1 month with minimal neurologic impairment; among patients who received shocks from public-access AEDs, 31.6% were alive at 1 month with minimal neurologic impairment. Early defibrillation, regardless of the type of provider (bystander or emergency-medical-services personnel), was associated with a good neurologic outcome after a cardiac arrest with ventricular fibrillation (adjusted odds ratio per 1-minute increase in the time to administration of shock, 0.91; 95% confidence interval, 0.89 to 0.92; P<0.001). The mean time to shock was reduced from 3.7 to 2.2 minutes, and the annual number of patients per 10 million population who survived with minimal neurologic impairment increased from 2.4 to 8.9 as the number of public-access AEDs increased from fewer than 1 per square kilometer of inhabited area to 4 or more. <br /><b>Conclusions:</b><br/>Nationwide dissemination of public-access AEDs in Japan resulted in earlier administration of shocks by laypersons and in an increase in the 1-month rate of survival with minimal neurologic impairment after an out-of-hospital cardiac arrest.<br /><br /><small>N Engl J Med: 18 Mar 2010; 362:994-1004</small></div>
Kitamura T, Iwami T, Kawamura T, Nagao K, ... Hiraide A, Implementation Working Group for the All-Japan Utstein Registry of the Fire and Disaster Management Agency
N Engl J Med: 18 Mar 2010; 362:994-1004 | PMID: 20237345
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<div><h4>Severe hypoglycemia and risks of vascular events and death.</h4><i>Zoungas S, Patel A, Chalmers J, de Galan BE, ... Heller S, ADVANCE Collaborative Group</i><br />BACKGROUND: Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. <br /><b>Methods:</b><br/>We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. <br /><b>Results:</b><br/>During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. <br /><b>Conclusions:</b><br/>Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.).<br /><br /><small>N Engl J Med: 07 Oct 2010; 363:1410-8</small></div>
Zoungas S, Patel A, Chalmers J, de Galan BE, ... Heller S, ADVANCE Collaborative Group
N Engl J Med: 07 Oct 2010; 363:1410-8 | PMID: 20925543
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<div><h4>Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults.</h4><i>Selvin E, Steffes MW, Zhu H, Matsushita K, ... Coresh J, Brancati FL</i><br />BACKGROUND: Fasting glucose is the standard measure used to diagnose diabetes in the United States. Recently, glycated hemoglobin was also recommended for this purpose. <br /><b>Methods:</b><br/>We compared the prognostic value of glycated hemoglobin and fasting glucose for identifying adults at risk for diabetes or cardiovascular disease. We measured glycated hemoglobin in whole-blood samples from 11,092 black or white adults who did not have a history of diabetes or cardiovascular disease and who attended the second visit (occurring in the 1990-1992 period) of the Atherosclerosis Risk in Communities (ARIC) study. <br /><b>Results:</b><br/>The glycated hemoglobin value at baseline was associated with newly diagnosed diabetes and cardiovascular outcomes. For glycated hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariable-adjusted hazard ratios (with 95% confidence intervals) for diagnosed diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48 (3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23 (1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The hazard ratios for stroke were similar. In contrast, glycated hemoglobin and death from any cause were found to have a J-shaped association curve. All these associations remained significant after adjustment for the baseline fasting glucose level. The association between the fasting glucose levels and the risk of cardiovascular disease or death from any cause was not significant in models with adjustment for all covariates as well as glycated hemoglobin. For coronary heart disease, measures of risk discrimination showed significant improvement when glycated hemoglobin was added to models including fasting glucose. <br /><b>Conclusions:</b><br/>In this community-based population of nondiabetic adults, glycated hemoglobin was similarly associated with a risk of diabetes and more strongly associated with risks of cardiovascular disease and death from any cause as compared with fasting glucose. These data add to the evidence supporting the use of glycated hemoglobin as a diagnostic test for diabetes. Copyright 2010 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 04 Mar 2010; 362:800-811</small></div>
Selvin E, Steffes MW, Zhu H, Matsushita K, ... Coresh J, Brancati FL
N Engl J Med: 04 Mar 2010; 362:800-811 | PMID: 20200384
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<div><h4>Two-Year Outcomes of Surgical Treatment of Severe Ischemic Mitral Regurgitation.</h4><i>Goldstein D, Moskowitz AJ, Gelijns AC, Ailawadi G, ... Acker MA, CTSN</i><br /><b>Background:</b><br/>In a randomized trial comparing mitral-valve repair with mitral-valve replacement in patients with severe ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI), survival, or adverse events at 1 year after surgery. However, patients in the repair group had significantly more recurrences of moderate or severe mitral regurgitation. We now report the 2-year outcomes of this trial. Methods We randomly assigned 251 patients to mitral-valve repair or replacement. Patients were followed for 2 years, and clinical and echocardiographic outcomes were assessed. Results Among surviving patients, the mean (±SD) 2-year LVESVI was 52.6±27.7 ml per square meter of body-surface area with mitral-valve repair and 60.6±39.0 ml per square meter with mitral-valve replacement (mean changes from baseline, -9.0 ml per square meter and -6.5 ml per square meter, respectively). Two-year mortality was 19.0% in the repair group and 23.2% in the replacement group (hazard ratio in the repair group, 0.79; 95% confidence interval, 0.46 to 1.35; P=0.39). The rank-based assessment of LVESVI at 2 years (incorporating deaths) showed no significant between-group difference (z score=-1.32, P=0.19). The rate of recurrence of moderate or severe mitral regurgitation over 2 years was higher in the repair group than in the replacement group (58.8% vs. 3.8%, P<0.001). There were no significant between-group differences in rates of serious adverse events and overall readmissions, but patients in the repair group had more serious adverse events related to heart failure (P=0.05) and cardiovascular readmissions (P=0.01). On the Minnesota Living with Heart Failure questionnaire, there was a trend toward greater improvement in the replacement group (P=0.07). <br /><b>Conclusions:</b><br/>In patients undergoing mitral-valve repair or replacement for severe ischemic mitral regurgitation, we observed no significant between-group difference in left ventricular reverse remodeling or survival at 2 years. Mitral regurgitation recurred more frequently in the repair group, resulting in more heart-failure-related adverse events and cardiovascular admissions. (Funded by the National Institutes of Health and Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00807040 .).<br /><br /><small>N Engl J Med: 08 Nov 2015; epub ahead of print</small></div>
Goldstein D, Moskowitz AJ, Gelijns AC, Ailawadi G, ... Acker MA, CTSN
N Engl J Med: 08 Nov 2015; epub ahead of print | PMID: 26550689
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<div><h4>A Leadless Intracardiac Transcatheter Pacing System.</h4><i>Reynolds D, Duray GZ, Omar R, Soejima K, ... Ritter P, Micra Transcatheter Pacing Study Group</i><br /><b>Background:</b><br/>A leadless intracardiac transcatheter pacing system has been designed to avoid the need for a pacemaker pocket and transvenous lead. Methods In a prospective multicenter study without controls, a transcatheter pacemaker was implanted in patients who had guideline-based indications for ventricular pacing. The analysis of the primary end points began when 300 patients reached 6 months of follow-up. The primary safety end point was freedom from system-related or procedure-related major complications. The primary efficacy end point was the percentage of patients with low and stable pacing capture thresholds at 6 months (≤2.0 V at a pulse width of 0.24 msec and an increase of ≤1.5 V from the time of implantation). The safety and efficacy end points were evaluated against performance goals (based on historical data) of 83% and 80%, respectively. We also performed a post hoc analysis in which the rates of major complications were compared with those in a control cohort of 2667 patients with transvenous pacemakers from six previously published studies. Results The device was successfully implanted in 719 of 725 patients (99.2%). The Kaplan-Meier estimate of the rate of the primary safety end point was 96.0% (95% confidence interval [CI], 93.9 to 97.3; P<0.001 for the comparison with the safety performance goal of 83%); there were 28 major complications in 25 of 725 patients, and no dislodgements. The rate of the primary efficacy end point was 98.3% (95% CI, 96.1 to 99.5; P<0.001 for the comparison with the efficacy performance goal of 80%) among 292 of 297 patients with paired 6-month data. Although there were 28 major complications in 25 patients, patients with transcatheter pacemakers had significantly fewer major complications than did the control patients (hazard ratio, 0.49; 95% CI, 0.33 to 0.75; P=0.001). <br /><b>Conclusions:</b><br/>In this historical comparison study, the transcatheter pacemaker met the prespecified safety and efficacy goals; it had a safety profile similar to that of a transvenous system while providing low and stable pacing thresholds. (Funded by Medtronic; Micra Transcatheter Pacing Study ClinicalTrials.gov number, NCT02004873 .).<br /><br /><small>N Engl J Med: 08 Nov 2015; epub ahead of print</small></div>
Reynolds D, Duray GZ, Omar R, Soejima K, ... Ritter P, Micra Transcatheter Pacing Study Group
N Engl J Med: 08 Nov 2015; epub ahead of print | PMID: 26551877
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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>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>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>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>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>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>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>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>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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Abstract
<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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This program is still in alpha version.