Journal: JAMA

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Abstract

Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women With Prior Hysterectomy: A Randomized Controlled Trial.

Lacroix AZ, Chlebowski RT, Manson JE, Aragaki AK, ... Wactawski-Wende J, for the WHI Investigators
Context The Women\'s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported. Objective To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009. Design, Setting, and Participants The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent. Main Outcome Measures The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death. Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction). Conclusions Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted. Trial registration clinicaltrials.gov Identifier: NCT00000611.

JAMA: 06 Apr 2011; 305:1305-1314
Lacroix AZ, Chlebowski RT, Manson JE, Aragaki AK, ... Wactawski-Wende J, for the WHI Investigators
JAMA: 06 Apr 2011; 305:1305-1314 | PMID: 21467283
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Abstract

Trends in Cardiovascular Health Metrics and Associations With All-Cause and CVD Mortality Among US Adults.

Yang Q, Cogswell ME, Flanders WD, Hong Y, ... Merritt R, Hu FB
Context Recent recommendations from the American Heart Association aim to improve cardiovascular health by encouraging the general population to meet 7 cardiovascular health metrics: not smoking; being physically active; having normal blood pressure, blood glucose and total cholesterol levels, and weight; and eating a healthy diet.Objective To examine time trends in cardiovascular health metrics and to estimate joint associations and population-attributable fractions of these metrics in relation to all-cause and cardiovascular disease (CVD) mortality risk.Design, Setting, and Participants Study of a nationally representative sample of 44 959 US adults (≥20 years), using data from the National Health and Nutrition Examination Survey (NHANES) 1988-1994, 1999-2004, and 2005-2010 and the NHANES III Linked Mortality File (through 2006).Main Outcome Measures All-cause, CVD, and ischemic heart disease (IHD) mortality.Results Few participants met all 7 cardiovascular health metrics (2.0% [95% CI, 1.5%-2.5%] in 1988-1994, 1.2% [95% CI, 0.8%-1.9%] in 2005-2010). Among NHANES III participants, 2673 all-cause, 1085 CVD, and 576 IHD deaths occurred (median follow-up, 14.5 years). Among participants who met 1 or fewer cardiovascular health metrics, age- and sex-standardized absolute risks were 14.8 (95% CI, 13.2-16.5) deaths per 1000 person-years for all-cause mortality, 6.5 (95% CI, 5.5-7.6) for CVD mortality, and 3.7 (95% CI, 2.8-4.5) for IHD mortality. Among those who met 6 or more metrics, corresponding risks were 5.4 (95% CI, 3.6-7.3) for all-cause mortality, 1.5 (95% CI, 0.5-2.5) for CVD mortality, and 1.1 (95% CI, 0.7-2.0) for IHD mortality. Adjusted hazard ratios were 0.49 (95% CI, 0.33-0.74) for all-cause mortality, 0.24 (95% CI, 0.13-0.47) for CVD mortality, and 0.30 (95% CI, 0.13-0.68) for IHD mortality, comparing participants who met 6 or more vs 1 or fewer cardiovascular health metrics. Adjusted population-attributable fractions were 59% (95% CI, 33%-76%) for all-cause mortality, 64% (95% CI, 28%-84%) for CVD mortality, and 63% (95% CI, 5%-89%) for IHD mortality.Conclusion Meeting a greater number of cardiovascular health metrics was associated with a lower risk of total and CVD mortality, but the prevalence of meeting all 7 cardiovascular health metrics was low in the study population.

JAMA: 18 Mar 2012; epub ahead of print
Yang Q, Cogswell ME, Flanders WD, Hong Y, ... Merritt R, Hu FB
JAMA: 18 Mar 2012; epub ahead of print | PMID: 22427615
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Abstract

Statewide newborn screening for severe T-cell lymphopenia.

Routes JM, Grossman WJ, Verbsky J, Laessig RH, ... Brokopp CD, Baker MW
Context: A newborn blood screening (NBS) test that could identify infants with a profound deficiency of T cells may result in a reduction in mortality. Objective: To determine if quantitating T-cell receptor excision circles (TRECs) using real-time quantitative polymerase chain reaction on DNA extracted from dried blood spots on NBS cards can detect infants with T-cell lymphopenia in a statewide program. Design, setting, and participants: Between January 1 and December 31, 2008, the Wisconsin State Laboratory of Hygiene screened all infants born in Wisconsin for T-cell lymphopenia by quantitating the number of TRECs contained in a 3.2-mm punch (approximately 3 microL of whole blood) of the NBS card. Flow cytometry to enumerate the number of T cells was performed on full-term infants and preterm infants when they reached the equivalent of at least 37 weeks\' gestation with TREC values of less than 25/microL. Infants with T-cell lymphopenia were evaluated by a clinical immunologist. Main outcome measures: The number of infants with TREC values of less than 25/microL with T-cell lymphopenia confirmed by flow cytometry. Results: Exactly 71,000 infants were screened by the TREC assay. Seventeen infants aged at least 37 weeks\' gestation had at least 1 abnormal TREC assay (TREC values < 25/microL), 11 of whom had samples analyzed by flow cytometry to enumerate T cells. Eight infants demonstrated T-cell lymphopenia. The causes of the T-cell lymphopenia included DiGeorge syndrome (n = 2), idiopathic T-cell lymphopenia (n = 2), extravascular extravasation of lymphocytes (n = 3), and a Rac2 mutation (n = 1). The infant with the Rac2 mutation underwent successful cord blood transplantation. Conclusion: In a statewide screening program, use of the TREC assay performed on NBS cards was able to identify infants with T-cell lymphopenia.

JAMA: 09 Dec 2009; 302:2465-70
Routes JM, Grossman WJ, Verbsky J, Laessig RH, ... Brokopp CD, Baker MW
JAMA: 09 Dec 2009; 302:2465-70 | PMID: 19996402
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Abstract

Association Between Timeliness of Reperfusion Therapy and Clinical Outcomes in ST-Elevation Myocardial Infarction.

Lambert L, Brown K, Segal E, Brophy J, Rodes-Cabau J, Bogaty P
Context: Guidelines emphasize the importance of rapid reperfusion of patients with ST-elevation myocardial infarction (STEMI) and specify a maximum delay of 30 minutes for fibrinolysis and 90 minutes for primary percutaneous coronary intervention (PPCI). However, randomized trials and selective registries are limited in their ability to assess the effect of timeliness of reperfusion on outcomes in real-world STEMI patients. ObjectiveS: To obtain a complete interregional portrait of contemporary STEMI care and to investigate timeliness of reperfusion and outcomes. Design, Setting, and PATIENTS: Systematic evaluation of STEMI care for 6 months during 2006-2007 in 80 hospitals that treated more than 95% of patients with acute myocardial infarction in the province of Quebec, Canada (population, 7.8 million). Main outcome measures: Death at 30 days and at 1 year and the combined end point of death or hospital readmission for acute myocardial infarction or congestive heart failure at 1 year by linkage to Quebec\'s medicoadministrative databases. Results: Of 1832 patients treated with reperfusion, 392 (21.4%) received fibrinolysis and 1440 (78.6%) received PPCI. Fibrinolysis was untimely (>30 minutes) in 54% and PPCI was untimely (>90 minutes) in 68%. Death or readmission for acute myocardial infarction or heart failure at 1 year occurred in 13.5% of fibrinolysis patients and 13.6% of PPCI patients. When the 2 treatment groups were combined, patients treated outside of recommended delays had an adjusted higher risk of death at 30 days (6.6% vs 3.3%; odds ratio [OR], 2.14; 95% confidence interval [CI], 1.21-3.93) and a statistically nonsignificant increase in risk of death at 1 year (9.3% vs 5.2%; OR, 1.61; 95% CI, 1.00-2.66) compared with patients who received timely treatment. Patients treated outside of recommended delays also had an adjusted higher risk for the combined outcome of death or hospital readmission for congestive heart failure or acute myocardial infarction at 1 year (15.0% vs 9.2%; OR, 1.57; 95% CI, 1.08-2.30). At the regional level, after adjustment, each 10% increase in patients treated within the recommended time was associated with a decrease in the region-level odds of overall 30-day mortality (OR, 0.80; 95% CI, 0.65-0.98). Conclusion: Among patients in Quebec with STEMI, reperfusion delivered outside guideline-recommend delays was associated with significantly increased 30-day mortality, a statistically nonsignificant increase in 1-year mortality, and significantly increased risk of the composite of mortality or readmission for acute myocardial infarction or heart failure at 1 year.

JAMA: 02 Jun 2010; 303:2148-55
Lambert L, Brown K, Segal E, Brophy J, Rodes-Cabau J, Bogaty P
JAMA: 02 Jun 2010; 303:2148-55 | PMID: 20516415
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Abstract

Association between carrier screening and incidence of cystic fibrosis.

Castellani C, Picci L, Tamanini A, Girardi P, Rizzotti P, Assael BM
Context: A downward trend in cystic fibrosis (CF) birth incidence has been reported in some areas. Objective: To evaluate the association between carrier screening and CF birth incidence. Design, setting, and participants: In northeastern Italy, CF birth incidence is monitored by means of a long-standing neonatal screening program. In the same area, 2 sections using different carrier detection approaches were identified--the western region, in which CF carrier tests are offered only to relatives of patients or to couples planning in vitro fertilization; and the eastern region, in which carrier testing is offered to relatives and carrier screening to infertile couples and to couples of reproductive age. A total of 779,631 newborns underwent CF neonatal screening between January 1993 and December 2007, of whom 195 had CF detected. Main outcome measure: Cystic fibrosis birth incidence in the 2 regions. Results: A time-related decrease in birth incidence was found, with a mean annual percentage decrease of 0.16 per 10,000 neonates (P < .001). In the western region, 2559 carrier tests were performed, 314 carriers were identified, and 9 carrier couples were detected. In the eastern region, 87,025 carrier tests were performed, 3650 carriers were identified, and 82 carrier couples were detected. The birth rate decrease was greater in the eastern region (decrease rate, 0.24; 95% confidence interval [CI], 0.12-0.36) than in the western region (decrease rate, 0.04; 95% CI, -0.16 to 0.08; P = .01). The increase in the number of screened carriers over time was significantly correlated with the decrease in CF birth incidence (correlation coefficient = -0.53; 95% CI, -0.20 to -0.74; P = .003). Conclusion: In northeastern Italy, carrier screening was associated with a decrease in the incidence of CF.

JAMA: 16 Dec 2009; 302:2573-9
Castellani C, Picci L, Tamanini A, Girardi P, Rizzotti P, Assael BM
JAMA: 16 Dec 2009; 302:2573-9 | PMID: 20009057
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Abstract

Coronary artery calcium score and risk classification for coronary heart disease prediction.

Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, ... Guerci AD, Greenland P
Context: The coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear. Objective: To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk. Design, setting, and participants: CACS was measured by computed tomography in 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded from the primary analysis. Five-year risk estimates for incident CHD were categorized as 0% to less than 3%, 3% to less than 10%, and 10% or more using Cox proportional hazards models. Model 1 used age, sex, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement and compared the distribution of risk using model 2 vs model 1. Main outcome measures: Incident CHD events. Results: During a median of 5.8 years of follow-up among a final cohort of 5878, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared with model 1 (net reclassification improvement = 0.25; 95% confidence interval, 0.16-0.34; P < .001). In model 1, 69% of the cohort was classified in the highest or lowest risk categories compared with 77% in model 2. An additional 23% of those who experienced events were reclassified as high risk, and an additional 13% without events were reclassified as low risk using model 2. Conclusion: In this multi-ethnic cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.

JAMA: 28 Apr 2010; 303:1610-6
Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, ... Guerci AD, Greenland P
JAMA: 28 Apr 2010; 303:1610-6 | PMID: 20424251
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Abstract

Three vs Twelve Months of Dual Antiplatelet Therapy After Zotarolimus-Eluting Stents: The OPTIMIZE Randomized Trial.

Feres F, Costa RA, Abizaid A, Leon MB, ... Bhatt DL, for the OPTIMIZE Trial Investigators
IMPORTANCE The current recommendation is for at least 12 months of dual antiplatelet therapy after implantation of a drug-eluting stent. However, the optimal duration of dual antiplatelet therapy with specific types of drug-eluting stents remains unknown. Objective To assess the clinical noninferiority of 3 months (short-term) vs 12 months (long-term) of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) with zotarolimus-eluting stents. Design, setting, and patients The OPTIMIZE trial was an open-label, active-controlled, 1:1 randomized noninferiority study including 3119 patients in 33 sites in Brazil between April 2010 and March 2012. Clinical follow-up was performed at 1, 3, 6, and 12 months. Eligible patients were those with stable coronary artery disease or history of low-risk acute coronary syndrome (ACS) undergoing PCI with zotarolimus-eluting stents. INTERVENTIONS After PCI with zotarolimus-eluting stents, patients were prescribed aspirin (100-200 mg daily) and clopidogrel (75 mg daily) for 3 months (n = 1563) or 12 months (n = 1556), unless contraindicated because of occurrence of an end point. MAIN OUTCOMES AND MEASURES The primary end point was net adverse clinical and cerebral events (NACCE; a composite of all-cause death, myocardial infarction [MI], stroke, or major bleeding); the expected event rate at 1 year was 9%, with a noninferiority margin of 2.7%. Secondary end points were major adverse cardiac events (MACE; a composite of all-cause death, MI, emergent coronary artery bypass graft surgery, or target lesion revascularization) and Academic Research Consortium definite or probable stent thrombosis. RESULTS NACCE occurred in 93 patients receiving short-term and 90 patients receiving long-term therapy (6.0% vs 5.8%, respectively; risk difference, 0.17 [95% CI, -1.52 to 1.86]; P = .002 for noninferiority). Kaplan-Meier estimates demonstrated MACE rates at 1 year of 8.3% (128) in the short-term group and 7.4% (114) in the long-term group (HR, 1.12 [95% CI, 0.87-1.45]). Between 91 and 360 days, no statistically significant association was observed for NACCE (39 [2.6%] vs 38 [2.6%] for the short- and long-term groups, respectively; HR, 1.03 [95% CI, 0.66-1.60]), MACE (78 [5.3%] vs 64 [4.3%]; HR, 1.22 [95% CI, 0.88-1.70]), or stent thrombosis (4 [0.3%] vs 1 [0.1%]; HR, 3.97 [95% CI, 0.44-35.49]). CONCLUSIONS AND RELEVANCE In patients with stable coronary artery disease or low-risk ACS treated with zotarolimus-eluting stents, 3 months of dual antiplatelet therapy was noninferior to 12 months for NACCE, without significantly increasing the risk of stent thrombosis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01113372.

JAMA: 31 Oct 2013; epub ahead of print
Feres F, Costa RA, Abizaid A, Leon MB, ... Bhatt DL, for the OPTIMIZE Trial Investigators
JAMA: 31 Oct 2013; epub ahead of print | PMID: 24177257
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Abstract

Effect of a Multifaceted Intervention on Use of Evidence-Based Therapies in Patients With Acute Coronary Syndromes in Brazil: The BRIDGE-ACS Randomized Trial.

Berwanger O, Guimarães HP, Laranjeira LN, Cavalcanti AB, ... Lopes RD, for the BRIDGE-ACS Investigators
Context Studies have found that patients with acute coronary syndromes (ACS) often do not receive evidence-based therapies in community practice. This is particularly true in low- and middle-income countries.Objective To evaluate whether a multifaceted quality improvement (QI) intervention can improve the use of evidence-based therapies and reduce the incidence of major cardiovascular events among patients with ACS in a middle-income country.Design, Setting, and Participants The BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes) trial, a cluster-randomized (concealed allocation) trial conducted among 34 clusters (public hospitals) in Brazil and enrolling a total of 1150 patients with ACS from March 15, 2011, through November 2, 2011, with follow-up through January 27, 2012.Intervention Multifaceted QI intervention including educational materials for clinicians, reminders, algorithms, and case manager training, vs routine practice (control).Main Outcome Measures Primary end point was the percentage of eligible patients who received all evidence-based therapies (aspirin, clopidogrel, anticoagulants, and statins) during the first 24 hours in patients without contraindications.Results Mean age of the patients enrolled was 62 (SD, 13) years; 68.6% were men, and 40% presented with ST-segment elevation myocardial infarction, 35.6% with non-ST-segment elevation myocardial infarction, and 23.6% with unstable angina. The randomized clusters included 79.5% teaching hospitals, all from major urban areas and 41.2% with 24-hour percutaneous coronary intervention capabilities. Among eligible patients (923/1150 [80.3%]), 67.9% in the intervention vs 49.5% in the control group received all eligible acute therapies (population average odds ratio [OR(PA)], 2.64 [95% CI, 1.28-5.45]). Similarly, among eligible patients (801/1150 [69.7%]), those in the intervention group were more likely to receive all eligible acute and discharge medications (50.9% vs 31.9%; OR(PA),(,) 2.49 [95% CI, 1.08-5.74]). Overall composite adherence scores were higher in the intervention clusters (89% vs 81.4%; mean difference, 8.6% [95% CI, 2.2%-15.0%]). In-hospital cardiovascular event rates were 5.5% in the intervention group vs 7.0% in the control group (OR(PA), 0.72 [95% CI, 0.36-1.43]); 30-day all-cause mortality was 7.0% vs 8.4% (OR(PA), 0.79 [95% CI, 0.46-1.34]).Conclusion Among patients with ACS treated in Brazil, a multifaceted educational intervention resulted in significant improvement in the use of evidence-based therapies.Trial registration clinicaltrials.gov Identifier: NCT00958958.

JAMA: 25 Mar 2012; epub ahead of print
Berwanger O, Guimarães HP, Laranjeira LN, Cavalcanti AB, ... Lopes RD, for the BRIDGE-ACS Investigators
JAMA: 25 Mar 2012; epub ahead of print | PMID: 22447889
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Abstract

Automated External Defibrillators and Survival After In-Hospital Cardiac Arrest.

Chan PS, Krumholz HM, Spertus JA, Jones PG, ... Nallamothu BK, for the American Heart Association National Registry of Cardiopulmonary Resuscitation (NRCPR) Investigators
Context: Automated external defibrillators (AEDs) improve survival from out-of-hospital cardiac arrests, but data on their effectiveness in hospitalized patients are limited. Objective: To evaluate the association between AED use and survival for in-hospital cardiac arrest. Design, Setting, and PATIENTS: Cohort study of 11 695 hospitalized patients with cardiac arrests between January 1, 2000, and August 26, 2008, at 204 US hospitals following the introduction of AEDs on general hospital wards. Main outcome measure: Survival to hospital discharge by AED use, using multivariable hierarchical regression analyses to adjust for patient factors and hospital site. Results: Of 11 695 patients, 9616 (82.2%) had nonshockable rhythms (asystole and pulseless electrical activity) and 2079 (17.8%) had shockable rhythms (ventricular fibrillation and pulseless ventricular tachycardia). AEDs were used in 4515 patients (38.6%). Overall, 2117 patients (18.1%) survived to hospital discharge. Within the entire study population, AED use was associated with a lower rate of survival after in-hospital cardiac arrest compared with no AED use (16.3% vs 19.3%; adjusted rate ratio [RR], 0.85; 95% confidence interval [CI], 0.78-0.92; P < .001). Among cardiac arrests due to nonshockable rhythms, AED use was associated with lower survival (10.4% vs 15.4%; adjusted RR, 0.74; 95% CI, 0.65-0.83; P < .001). In contrast, for cardiac arrests due to shockable rhythms, AED use was not associated with survival (38.4% vs 39.8%; adjusted RR, 1.00; 95% CI, 0.88-1.13; P = .99). These patterns were consistently observed in both monitored and nonmonitored hospital units where AEDs were used, after matching patients to the individual units in each hospital where the cardiac arrest occurred, and with a propensity score analysis. Conclusion: Among hospitalized patients with cardiac arrest, use of AEDs was not associated with improved survival.

JAMA: 17 Nov 2010; 304:2129-2136
Chan PS, Krumholz HM, Spertus JA, Jones PG, ... Nallamothu BK, for the American Heart Association National Registry of Cardiopulmonary Resuscitation (NRCPR) Investigators
JAMA: 17 Nov 2010; 304:2129-2136 | PMID: 21078809
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Abstract

Association of myocardial enzyme elevation and survival following coronary artery bypass graft surgery.

Domanski MJ, Mahaffey K, Hasselblad V, Brener SJ, ... Pieper KS, Farkouh ME
Context Several small studies have suggested that cardiac enzyme elevation in the 24 hours following coronary artery bypass graft (CABG) surgery is associated with worse prognosis, but a definitive study is not available. Also, the long-term prognostic impact of small increases of perioperative enzyme has not been reported. Objective To quantify the relationship between peak post-CABG elevation of biomarkers of myocardial damage and early, intermediate-, and long-term mortality, including determining whether there is a threshold below which elevations lack prognostic significance. Data Sources Studies (randomized clinical trials or registries) of patients undergoing CABG surgery in which postprocedural biomarker and mortality data were collected and included. A search of the PubMed database was performed in July 2008 using the search terms coronary artery bypass, troponin, CK-MB, and mortality. Study Selection Studies evaluating mortality and creatine kinase (CK-MB), troponin, or both were included. One study investigator declined to participate and 3 had insufficient data. Data Extraction Two independent reviewers determined study eligibility. The principal investigator from each eligible study was contacted to request his/her participation. Once institutional review board approval for the use of these data for this purpose was obtained, we requested patient-level data from each source. Data were examined to ensure that cardiac markers had been measured within 24 hours after CABG surgery, key baseline covariates, and mortality were available. Results A total of 18 908 patients from 7 studies were included. Follow-up varied from 3 months to 5 years. Mortality was found to be a monotonically increasing function of the CK-MB ratio. The 30-day mortality rates by categories of CK-MB ratio were 0.63% (95% confidence interval [CI], 0.36%-1.02%) for 0 to <1, 0.86% (95% CI, 0.49%-1.40%) for 1 to <2, 0.95% (95% CI, 0.72%-1.22%) for 2 to <5, 2.09% (95% CI, 1.69%-2.57%) for 5 to <10, 2.78% (95% CI, 2.12%-3.58%) for 10 to <20, and 7.06% (95% CI, 5.46%-8.96%) for 20 to ≥40. Of the variables considered, the CK-MB ratio was the strongest independent predictor of death to 30 days and remained significant even after adjusting for a wide range of baseline risk factors (χ(2) = 143, P < .001; hazard ratio [HR] for each 5 point-increment above the upper limits of normal [ULN] = 1.12; 95% CI, 1.10-1.14). This result was strongest at 30 days, but the adjusted association persisted from 30 days to 1 year (χ(2) = 24; P < .001; HR for each 5-point increment above ULN = 1.17; 95% CI, 1.10-1.24) and a trend was present from 1 year to 5 years (χ(2) = 2.8; P = .10; HR for each 5-point increment above ULN = 1.05; 95% CI, 0.99-1.11). Similar analyses using troponin as the marker of necrosis led to the same conclusions (χ(2) = 142 for 0-30 days and χ(2) = 40 for 30 days to 6 months, both P < .001; HR for each 50 points above the ULN = 1.28; 95% CI, 1.23-1.33 and 1.15; 95% CI, 1.10-1.21, respectively). Conclusions Among patients who had undergone CABG surgery, elevation of CK-MB or troponin levels within the first 24 hours was independently associated with increased intermediate- and long-term risk of mortality.

JAMA: 09 Feb 2011; 305:585-91
Domanski MJ, Mahaffey K, Hasselblad V, Brener SJ, ... Pieper KS, Farkouh ME
JAMA: 09 Feb 2011; 305:585-91 | PMID: 21304084
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Abstract

Contraindicated medication use in dialysis patients undergoing percutaneous coronary intervention.

Tsai TT, Maddox TM, Roe MT, Dai D, ... Rumsfeld JS,
Context: The US Food and Drug Administration guides clinicians through drug labeling of medications that are contraindicated or not recommended for use in specific patient groups. Little is known about the use of such medications and their effects on outcomes in clinical practice. Objective: To investigate the use of the contraindicated/not-recommended agents enoxaparin and eptifibatide among dialysis patients undergoing percutaneous coronary intervention (PCI) and their association with outcomes. Design, setting, and participants: Data from 829 US hospitals on 22 778 dialysis patients who underwent PCI between January 1, 2004, and August 31, 2008. Main outcome measures: In-hospital bleeding and death. Results: Five thousand eighty-four patients (22.3%) received a contraindicated antithrombotic; of these patients, 2375 (46.7%) received enoxaparin, 3261 (64.1%) received eptifibatide, and 552 (10.9%) received both. Compared with patients who did not receive a contraindicated antithrombotic, patients who did had higher rates of in-hospital bleeding (5.6% vs 2.9%; odds ratio [OR], 1.93; 95% confidence interval [CI],1.66-2.23) and death (6.5% vs 3.9%; OR, 1.68; 95% CI, 1.46-1.95). After multivariable adjustment, patients receiving contraindicated antithrombotics had significantly higher risks of in-hospital bleeding (OR, 1.66; 95% CI, 1.43-1.92) and death (OR, 1.24; 95% CI, 1.04-1.48). In 10 158 patients matched by propensity scores, receipt of contraindicated antithrombotics remained significantly associated with in-hospital bleeding (OR, 1.63; 95% CI, 1.35-1.98) but not in-hospital death (OR, 1.15; 95% CI, 0.97-1.36). Conclusions: In a sample of dialysis patients undergoing PCI, 22.3% received a contraindicated antithrombotic medication. In propensity-matched analysis, receipt of these medications was significantly associated with an increased risk of in-hospital major bleeding.

JAMA: 09 Dec 2009; 302:2458-64
Tsai TT, Maddox TM, Roe MT, Dai D, ... Rumsfeld JS,
JAMA: 09 Dec 2009; 302:2458-64 | PMID: 19996401
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Abstract

Automated surveillance to detect postprocedure safety signals of approved cardiovascular devices.

Resnic FS, Gross TP, Marinac-Dabic D, Loyo-Berrios N, ... Normand SL, Matheny ME
Context: Ensuring the safety of medical devices challenges current surveillance approaches, which rely heavily on voluntary reporting of adverse events. Automated surveillance of clinical registries may provide early warnings in the postmarket evaluation of medical device safety. Objective: To determine whether automated safety surveillance of clinical registries using a computerized tool can provide early warnings regarding the safety of new cardiovascular devices. Design, Setting, and PATIENTS: Prospective propensity-matched cohort analysis of 7 newly introduced cardiovascular devices, using clinical data captured in the Massachusetts implementation of the National Cardiovascular Data Repository CathPCI Registry for all adult patients undergoing percutaneous coronary intervention from April 2003 through September 2007 in Massachusetts. Main outcome measure: Presence of any safety alert, triggered if the cumulative observed risk for a given device exceeded the upper 95% confidence interval (CI) of comparator control device. Predefined sensitivity analyses assessed robustness of alerts when triggered. Results: We evaluated 74 427 consecutive interventional coronary procedures. Three of 21 safety analyses triggered sustained alerts in 2 implantable devices. Patients receiving Taxus Express2 drug-eluting stents experienced a 1.28-fold increased risk of postprocedural myocardial infarction (2.87% vs 2.25%; absolute risk increase, 0.62% [95% CI, 0.25%-0.99%]) and a 1.21-fold increased risk of major adverse cardiac events (4.24% vs 3.50%; absolute increase, 0.74% [95% CI, 0.29%-1.19%]) compared with those receiving alternative drug-eluting stents. Patients receiving Angio-Seal STS vascular closure devices experienced a 1.51-fold increased risk of major vascular complications (1.09% vs 0.72%; absolute increased risk, 0.37% [95% CI, 0.03%-0.71%]) compared with those receiving alternative vascular closure devices. Sensitivity analyses confirmed increased risk following use of the Taxus Express2 stent but not the Angio-Seal STS device. Conclusion: Automated prospective surveillance of clinical registries is feasible and can identify low-frequency safety signals for new cardiovascular devices.

JAMA: 10 Nov 2010; 304:2019-27
Resnic FS, Gross TP, Marinac-Dabic D, Loyo-Berrios N, ... Normand SL, Matheny ME
JAMA: 10 Nov 2010; 304:2019-27 | PMID: 21063011
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Abstract

Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction: The INFUSE-AMI Randomized Trial.

Stone GW, Maehara A, Witzenbichler B, Godlewski J, ... Gibson CM, for the INFUSE-AMI Investigators
Context Thrombus embolization during percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) is common and results in suboptimal myocardial perfusion and increased infarct size. Two strategies proposed to reduce distal embolization and improve outcomes after primary PCI are bolus intracoronary abciximab and manual aspiration thrombectomy.Objective To determine whether bolus intracoronary abciximab, manual aspiration thrombectomy, or both reduce infarct size in high-risk patients with STEMI.Design, Setting, and Patients Between November 28, 2009, and December 2, 2011, 452 patients presenting at 37 sites in 6 countries within 4 hours of STEMI due to proximal or mid left anterior descending artery occlusion undergoing primary PCI with bivalirudin anticoagulation were randomized in an open-label, 2 2 factorial design to bolus intracoronary abciximab delivered locally at the infarct lesion site vs no abciximab and to manual aspiration thrombectomy vs no thrombectomy.Interventions A 0.25-mg/kg bolus of abciximab was administered at the site of the infarct lesion via a local drug delivery catheter. Manual aspiration thrombectomy was performed with a 6 F aspiration catheter.Main Outcome Measures Primary end point: infarct size (percentage of total left ventricular mass) at 30 days assessed by cardiac magnetic resonance imaging (cMRI) in the abciximab vs no abciximab groups (pooled across the aspiration randomization); major secondary end point: 30-day infarct size in the aspiration vs no aspiration groups (pooled across the abciximab randomization).Results Evaluable cMRI results at 30 days were present in 181 and 172 patients randomized to intracoronary abciximab vs no abciximab, respectively, and in 174 and 179 patients randomized to manual aspiration vs no aspiration, respectively. Patients randomized to intracoronary abciximab compared with no abciximab had a significant reduction in 30-day infarct size (median, 15.1%; interquartile range [IQR], 6.8%-22.7%; n = 181, vs 17.9% [IQR, 10.3%-25.4%]; n = 172; P = .03). Patients randomized to intracoronary abciximab also had a significant reduction in absolute infarct mass (median, 18.7 g [IQR, 7.4-31.3 g]; n = 184, vs 24.0 g [IQR, 12.1-34.2 g]; n = 175; P = .03) but not abnormal wall motion score (median, 7.0 [IQR, 2.0-10.0]; n = 188, vs 8.0 [IQR, 3.0-10.0]; n = 184; P = .08). Patients randomized to aspiration thrombectomy vs no aspiration had no significant difference in infarct size at 30 days (median, 17.0% [IQR, 9.0%-22.8%]; n = 174, vs 17.3% [IQR, 7.1%-25.5%]; n = 179; P = .51), absolute infarct mass (median, 20.3 g [IQR, 9.7-31.7 g]; n = 178, vs 21.0 g [IQR, 9.1-34.1 g]; n = 181; P = .36), or abnormal wall motion score (median, 7.5 [IQR, 2.0-10.0]; n = 186, vs 7.5 [IQR, 2.0-10.0]; n = 186; P = .89).Conclusion In patients with large anterior STEMI presenting early after symptom onset and undergoing primary PCI with bivalirudin anticoagulation, infarct size at 30 days was significantly reduced by bolus intracoronary abciximab delivered to the infarct lesion site but not by manual aspiration thrombectomy.Trial registration clinicaltrials.gov Identifier: NCT00976521.

JAMA: 25 Mar 2012; epub ahead of print
Stone GW, Maehara A, Witzenbichler B, Godlewski J, ... Gibson CM, for the INFUSE-AMI Investigators
JAMA: 25 Mar 2012; epub ahead of print | PMID: 22447888
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Abstract

Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Heart Failure: The FOCUS-CCTRN Trial.

Perin EC, Willerson JT, Pepine CJ, Henry TD, ... Simari RD, for the Cardiovascular Cell Therapy Research Network (CCTRN)
Context Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.Objective To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina.Design, Setting, and Patients A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011.Intervention Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group).Main Outcome Measures Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory.Results Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement.Conclusion Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT.Trial registration clinicaltrials.gov Identifier: NCT00824005.

JAMA: 25 Mar 2012; epub ahead of print
Perin EC, Willerson JT, Pepine CJ, Henry TD, ... Simari RD, for the Cardiovascular Cell Therapy Research Network (CCTRN)
JAMA: 25 Mar 2012; epub ahead of print | PMID: 22447880
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Abstract

Calcium Density of Coronary Artery Plaque and Risk of Incident Cardiovascular Events.

Criqui MH, Denenberg JO, Ix JH, McClelland RL, ... Budoff MJ, Allison MA
IMPORTANCE Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD. Objective To determine the independent associations of CAC volume and CAC density with incident CVD events. Design, setting, and participants Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010. MAIN OUTCOMES AND MEASURES Incident coronary heart disease (CHD) and all CVD events RESULTS During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02. CONCLUSIONS AND RELEVANCE CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.

JAMA: 18 Nov 2013; epub ahead of print
Criqui MH, Denenberg JO, Ix JH, McClelland RL, ... Budoff MJ, Allison MA
JAMA: 18 Nov 2013; epub ahead of print | PMID: 24247483
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Abstract

Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile.

Martin SS, Blaha MJ, Elshazly MB, Toth PP, ... Blumenthal RS, Jones SR
IMPORTANCE In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels. Objective To derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio. Design, setting, and participants We used a convenience sample of consecutive clinical lipid profiles obtained from 2009 through 2011 from 1 350 908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after vertical spin density-gradient ultracentrifugation, and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (n = 900 605) and validation (n = 450 303) data sets. MAIN OUTCOMES AND MEASURES Individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD). RESULTS In the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 4.5-6.0). The triglyceride and non-high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non-HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%-91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (P &lt; .001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149 mg/dL; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199 mg/dL; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (P &lt; .001 for each comparison). CONCLUSIONS AND RELEVANCE A novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01698489.

JAMA: 17 Nov 2013; 310:2061-8
Martin SS, Blaha MJ, Elshazly MB, Toth PP, ... Blumenthal RS, Jones SR
JAMA: 17 Nov 2013; 310:2061-8 | PMID: 24240933
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Abstract

Coronary Artery Bypass Graft Surgery vs Percutaneous Interventions in Coronary Revascularization: A Systematic Review.

Deb S, Wijeysundera HC, Ko DT, Tsubota H, Hill S, Fremes SE
IMPORTANCE Ischemic heart disease is the leading cause of death globally. Coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) are the revascularization options for ischemic heart disease. However, the choice of the most appropriate revascularization modality is controversial in some patient subgroups. Objective To summarize the current evidence comparing the effectiveness of CABG surgery and PCI in patients with unprotected left main disease (ULMD, in which there is &gt;50% left main coronary stenosis without protective bypass grafts), multivessel coronary artery disease (CAD), diabetes, or left ventricular dysfunction (LVD). EVIDENCE REVIEW A search of OvidSP MEDLINE, EMBASE, and Cochrane databases between January 2007 and June 2013, limited to randomized clinical trials (RCTs) and meta-analysis of trials and/or observational studies comparing CABG surgery with PCI was performed. Bibliographies of relevant studies were also searched. Mortality and major adverse cardiac and cerebrovascular events (MACCE, defined as all-cause mortality, myocardial infarction, stroke, and repeat revascularization) were reported wherever possible. FINDINGS Thirteen RCTs and 5 meta-analyses were included. CABG surgery should be recommended in patients with ULMD, multivessel CAD, or LVD, if the severity of coronary disease is deemed to be complex (SYNTAX &gt;22) due to lower cardiac events associated with CABG surgery. In cases in which coronary disease is less complex (SYNTAX ≤22) and/or the patient is a higher surgical risk, PCI should be considered. For patients with diabetes and multivessel CAD, CABG surgery should be recommended as standard therapy irrespective of the severity of coronary anatomy, given improved long-term survival and lower cardiac events (5-year MACCE, 18.7% for CABG surgery vs 26.6% for PCI; P = .005). Overall, the incidence of repeat revascularization is higher after PCI, whereas stroke is higher after CABG surgery. Current literature emphasizes the importance of a heart-team approach that should consider coronary anatomy, patient characteristics, and local expertise in revascularization options. Literature pertaining to revascularization options in LVD is scarce predominantly due to LVD being an exclusion factor in most studies. CONCLUSIONS AND RELEVANCE Both CABG surgery and PCI are reasonable options for patients with advanced CAD. Patients with diabetes generally have better outcomes with CABG surgery than PCI. In cases of ULMD, multivessel CAD, or LVD, CABG surgery should be favored in patients with complex coronary lesions and anatomy and PCI in less complicated coronary disease or deemed a high surgical risk. A heart-team approach should evaluate coronary disease complexity, patient comorbidities, patient preferences, and local expertise.

JAMA: 17 Nov 2013; 310:2086-95
Deb S, Wijeysundera HC, Ko DT, Tsubota H, Hill S, Fremes SE
JAMA: 17 Nov 2013; 310:2086-95 | PMID: 24240936
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Abstract

Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with atrial fibrillation: a randomized clinical trial.

Abed HS, Wittert GA, Leong DP, Shirazi MG, ... Kalman JM, Sanders P
IMPORTANCE Obesity is a risk factor for atrial fibrillation. Whether weight reduction and cardiometabolic risk factor management can reduce the burden of atrial fibrillation is not known. Objective To determine the effect of weight reduction and management of cardiometabolic risk factors on atrial fibrillation burden and cardiac structure. Design, setting, and patients Single-center, partially blinded, randomized controlled study conducted between June 2010 and December 2011 in Adelaide, Australia, among overweight and obese ambulatory patients (N = 150) with symptomatic atrial fibrillation. Patients underwent a median of 15 months of follow-up. INTERVENTIONS Patients were randomized to weight management (intervention) or general lifestyle advice (control). Both groups underwent intensive management of cardiometabolic risk factors. MAIN OUTCOMES AND MEASURES The primary outcomes were Atrial Fibrillation Severity Scale scores: symptom burden and symptom severity. Scores were measured every 3 months from baseline to 15 months. Secondary outcomes performed at baseline and 12 months were total atrial fibrillation episodes and cumulative duration measured by 7-day Holter, echocardiographic left atrial area, and interventricular septal thickness. RESULTS Of 248 patients screened, 150 were randomized (75 per group) and underwent follow-up. The intervention group showed a significantly greater reduction, compared with the control group, in weight (14.3 and 3.6 kg, respectively; P &lt; .001) and in atrial fibrillation symptom burden scores (11.8 and 2.6 points, P &lt; .001), symptom severity scores (8.4 and 1.7 points, P &lt; .001), number of episodes (2.5 and no change, P = .01), and cumulative duration (692-minute decline and 419-minute increase, P = .002). Additionally, there was a reduction in interventricular septal thickness in the intervention and control groups (1.1 and 0.6 mm, P = .02) and left atrial area (3.5 and 1.9 cm2, P = .02). CONCLUSIONS AND RELEVANCE In this study, weight reduction with intensive risk factor management resulted in a reduction in atrial fibrillation symptom burden and severity and in beneficial cardiac remodeling. These findings support therapy directed at weight and risk factors in the management of atrial fibrillation. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12610000497000.

JAMA: 17 Nov 2013; 310:2050-60
Abed HS, Wittert GA, Leong DP, Shirazi MG, ... Kalman JM, Sanders P
JAMA: 17 Nov 2013; 310:2050-60 | PMID: 24240932
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Abstract

Medical care for the final years of life: "When you\'re 83, it\'s not going to be 20 years".

Reuben DB
The case of an 83-year-old man who has had a fall-related injury and continues to be the sole caregiver for his wife who has dementia exemplifies a common situation that clinicians face--planning for the final years of an elderly individual\'s life. To appropriately focus on the patient\'s most pressing issues, the approach should begin with an assessment of life expectancy and incorporation of evidence-based care whenever possible. Short-term issues are focused on efforts to restore the patient to his previous state of health. Mid-range issues address providing preventive care, identifying geriatric syndromes, and helping him cope with the psychosocial needs of being a caregiver. Long-term issues relate to planning for his eventual decline and meeting his goals for the end of life. Unfortunately, the workload and inefficiencies of primary care practice present barriers to providing optimal care for older patients. Systematic approaches, including team care, are needed to adequately manage chronic diseases and coordinate care.

JAMA: 30 Dec 2009; 302:2686-94
Reuben DB
JAMA: 30 Dec 2009; 302:2686-94 | PMID: 20040557
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Effect of Metformin on Left Ventricular Function After Acute Myocardial Infarction in Patients Without Diabetes: The GIPS-III Randomized Clinical Trial.

Lexis CP, van der Horst IC, Lipsic E, Wieringa WG, ... van Veldhuisen DJ, for the GIPS-III Investigators
IMPORTANCE Metformin treatment is associated with improved outcome after myocardial infarction in patients with diabetes. In animal experimental studies metformin preserves left ventricular function. Objective To evaluate the effect of metformin treatment on preservation of left ventricular function in patients without diabetes presenting with ST-segment elevation myocardial infarction (STEMI). Design, setting, and participants Double-blind, placebo-controlled study conducted among 380 patients who underwent primary percutaneous coronary intervention (PCI) for STEMI at the University Medical Center Groningen, the Netherlands, between January 1, 2011, and May 26, 2013. INTERVENTIONS Metformin hydrochloride (500 mg) (n = 191) or placebo (n = 189) twice daily for 4 months. MAIN OUTCOMES AND MEASURES The primary efficacy measure was left ventricular ejection fraction (LVEF) after 4 months, assessed by magnetic resonance imaging. A secondary efficacy measure was the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after 4 months. The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target-lesion revascularization) was recorded until 4 months as a secondary efficacy measure. RESULTS At 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%-54.6%) in the metformin group (n = 135), compared with 54.8% (95% CI, 53.5%-56.1%) (P = .10) in the placebo group (n = 136). NT-proBNP concentration was 167 ng/L in the metformin group (interquartile range [IQR], 65-393 ng/L) and 167 ng/L in the placebo group (IQR, 74-383 ng/L) (P = .66). MACE were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (P = .16). Creatinine concentration (79 µmol/L [IQR, 70-87 µmol/L] vs 79 µmol/L [IQR, 72-89 µmol/L], P = .61) and glycated hemoglobin (5.9% [IQR, 5.6%-6.1%] vs 5.9% [IQR, 5.7%-6.1%], P = .15) were not significantly different between both groups. No cases of lactic acidosis were observed. CONCLUSIONS AND RELEVANCE Among patients without diabetes presenting with STEMI and undergoing primary PCI, the use of metformin compared with placebo did not result in improved LVEF after 4 months. The present findings do not support the use of metformin in this setting. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01217307.

JAMA: 31 Mar 2014; epub ahead of print
Lexis CP, van der Horst IC, Lipsic E, Wieringa WG, ... van Veldhuisen DJ, for the GIPS-III Investigators
JAMA: 31 Mar 2014; epub ahead of print | PMID: 24687169
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Abstract

Association between a literature-based genetic risk score and cardiovascular events in women.

Paynter NP, Chasman DI, Paré G, Buring JE, ... Miletich JP, Ridker PM
Context: While multiple genetic markers associated with cardiovascular disease have been identified by genome-wide association studies, their aggregate effect on risk beyond traditional factors is uncertain, particularly among women. Objective: To test the predictive ability of a literature-based genetic risk score for cardiovascular disease. Design, setting, and participants: Prospective cohort of 19 313 initially healthy white women in the Women\'s Genome Health Study followed up over a median of 12.3 years (interquartile range, 11.6-12.8 years). Genetic risk scores were constructed from the National Human Genome Research Institute\'s catalog of genome-wide association study results published between 2005 and June 2009. Main outcome measure: Incident myocardial infarction, stroke, arterial revascularization, and cardiovascular death. Results: A total of 101 single nucleotide polymorphisms reported to be associated with cardiovascular disease or at least 1 intermediate cardiovascular disease phenotype at a published P value of less than 10(-7) were identified and risk alleles were added to create a genetic risk score. During follow-up, 777 cardiovascular disease events occurred (199 myocardial infarctions, 203 strokes, 63 cardiovascular deaths, 312 revascularizations). After adjustment for age, the genetic risk score had a hazard ratio (HR) for cardiovascular disease of 1.02 per risk allele (95% confidence interval [CI], 1.00-1.03/risk allele; P = .006). This corresponds to an absolute cardiovascular disease risk of 3% over 10 years in the lowest tertile of genetic risk (73-99 risk alleles) and 3.7% in the highest tertile (106-125 risk alleles). However, after adjustment for traditional factors, the genetic risk score did not improve discrimination or reclassification (change in c index from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [ATP III] risk score, 0; net reclassification improvement, 0.5%; [P = .24]). The genetic risk score was not associated with cardiovascular disease risk (ATP III-adjusted HR/allele, 1.00; 95% CI, 0.99-1.01). In contrast, self-reported family history remained significantly associated with cardiovascular disease in multivariable models. Conclusion: After adjustment for traditional cardiovascular risk factors, a genetic risk score comprising 101 single nucleotide polymorphisms was not significantly associated with the incidence of total cardiovascular disease.

JAMA: 17 Feb 2010; 303:631-7
Paynter NP, Chasman DI, Paré G, Buring JE, ... Miletich JP, Ridker PM
JAMA: 17 Feb 2010; 303:631-7 | PMID: 20159871
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Association Between Use of Bleeding Avoidance Strategies and Risk of Periprocedural Bleeding Among Patients Undergoing Percutaneous Coronary Intervention.

Marso SP, Amin AP, House JA, Kennedy KF, ... Rumsfeld JS, for the National Cardiovascular Data Registry
Context: Bleeding complications with percutaneous coronary intervention (PCI) are associated with adverse patient outcomes. The association between the use of bleeding avoidance strategies and post-PCI bleeding as a function of a patient\'s preprocedural risk of bleeding is unknown. Objective: To describe the use of 2 bleeding avoidance strategies, vascular closure devices and bivalirudin, and associated post-PCI bleeding rates in a nationally representative PCI population. Design, Setting, and PATIENTS: Analysis of data from 1 522 935 patients undergoing PCI procedures performed at 955 US hospitals participating in the National Cardiovascular Data Registry (NCDR) CathPCI Registry from January 1, 2004, through September 30, 2008. Main outcome measure: Periprocedural bleeding. Results: Bleeding occurred in 30 654 patients (2%). Manual compression, vascular closure devices, bivalirudin, or vascular closure devices plus bivalirudin were used in 35%, 24%, 23%, and 18% of patients, respectively. Bleeding events were reported in 2.8% of patients who received manual compression, compared with 2.1%, 1.6%, and 0.9% of patients receiving vascular closure devices, bivalirudin, and both strategies, respectively (P < .001). Bleeding rates differed by preprocedural risk assessed with the NCDR bleeding risk model (low risk, 0.72%; intermediate risk, 1.73%; high risk, 4.69%). In high-risk patients, use of both strategies was associated with lower bleeding rates (manual compression, 6.1%; vascular closure devices, 4.6%; bivalirudin, 3.8%; vascular closure devices plus bivalirudin, 2.3%; P < .001). This association persisted following adjustment using a propensity-matched and site-controlled model. Use of both strategies was used least often in high-risk patients (14.4% vs 21.0% in low-risk patients, P < .001). Conclusions: In a large national PCI registry, vascular closure devices and bivalirudin were associated with significantly lower bleeding rates, particularly among patients at greatest risk for bleeding. However, these strategies were less often used among higher-risk patients.

JAMA: 02 Jun 2010; 303:2156-2164
Marso SP, Amin AP, House JA, Kennedy KF, ... Rumsfeld JS, for the National Cardiovascular Data Registry
JAMA: 02 Jun 2010; 303:2156-2164 | PMID: 20516416
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Effect of a Perioperative, Cardiac Output-Guided Hemodynamic Therapy Algorithm on Outcomes Following Major Gastrointestinal Surgery: A Randomized Clinical Trial and Systematic Review.

Pearse RM, Harrison DA, MacDonald N, Gillies MA, ... Rowan K, for the OPTIMISE Study Group
IMPORTANCE Small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm. Objective To evaluate the clinical effectiveness of a perioperative, cardiac output-guided hemodynamic therapy algorithm. Design, setting, and participants OPTIMISE was a pragmatic, multicenter, randomized, observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom. An updated systematic review and meta-analysis were also conducted including randomized trials published from 1966 to February 2014. INTERVENTIONS Patients were randomly assigned to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope (dopexamine) infusion during and 6 hours following surgery (n=368) or to usual care (n=366). MAIN OUTCOMES AND MEASURES The primary outcome was a composite of predefined 30-day moderate or major complications and mortality. Secondary outcomes were morbidity on day 7; infection, critical care-free days, and all-cause mortality at 30 days; all-cause mortality at 180 days; and length of hospital stay. RESULTS Baseline patient characteristics, clinical care, and volumes of intravenous fluid were similar between groups. Care was nonadherent to the allocated treatment for less than 10% of patients in each group. The primary outcome occurred in 36.6% of intervention and 43.4% of usual care participants (relative risk [RR], 0.84 [95% CI, 0.71-1.01]; absolute risk reduction, 6.8% [95% CI, -0.3% to 13.9%]; P = .07). There was no significant difference between groups for any secondary outcomes. Five intervention patients (1.4%) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group. Findings of the meta-analysis of 38 trials, including data from this study, suggest that the intervention is associated with fewer complications (intervention, 488/1548 [31.5%] vs control, 614/1476 [41.6%]; RR, 0.77 [95% CI, 0.71-0.83]) and a nonsignificant reduction in hospital, 28-day, or 30-day mortality (intervention, 159/3215 deaths [4.9%] vs control, 206/3160 deaths [6.5%]; RR, 0.82 [95% CI, 0.67-1.01]) and mortality at longest follow-up (intervention, 267/3215 deaths [8.3%] vs control, 327/3160 deaths [10.3%]; RR, 0.86 [95% CI, 0.74-1.00]). CONCLUSIONS AND RELEVANCE In a randomized trial of high-risk patients undergoing major gastrointestinal surgery, use of a cardiac output-guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality. However, inclusion of these data in an updated meta-analysis indicates that the intervention was associated with a reduction in complication rates. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN04386758.

JAMA: 19 May 2014; epub ahead of print
Pearse RM, Harrison DA, MacDonald N, Gillies MA, ... Rowan K, for the OPTIMISE Study Group
JAMA: 19 May 2014; epub ahead of print | PMID: 24842135
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Abstract

US Trends in Prevalence, Awareness, Treatment, and Control of Hypertension, 1988-2008.

Egan BM, Zhao Y, Axon RN
Context: Hypertension is a major risk factor for cardiovascular disease and treatment and control of hypertension reduces risk. The Healthy People 2010 goal was to achieve blood pressure (BP) control in 50% of the US population. Objective: To assess progress in treating and controlling hypertension in the United States from 1988-2008. Design, setting, and participants: The National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2008 in five 2-year blocks included 42 856 adults aged older than 18 years, representing a probability sample of the US civilian population. Main outcome measures: Hypertension was defined as systolic BP of at least 140 mm Hg and diastolic BP of at least 90 mm Hg, self-reported use of antihypertensive medications, or both. Hypertension control was defined as systolic BP values of less than 140 mm Hg and diastolic BP values of less than 90 mm Hg. All survey periods were age-adjusted to the year 2000 US population. Results: Rates of hypertension increased from 23.9% (95% confidence interval [CI], 22.7%-25.2%) in 1988-1994 to 28.5% (95% CI, 25.9%-31.3%; P < .001) in 1999-2000, but did not change between 1999-2000 and 2007-2008 (29.0%; 95% CI, 27.6%-30.5%; P = .24). Hypertension control increased from 27.3% (95% CI, 25.6%-29.1%) in 1988-1994 to 50.1% (95% CI, 46.8%-53.5%; P = .006) in 2007-2008, and BP among patients with hypertension decreased from 143.0/80.4 mm Hg (95% CI, 141.9-144.2/79.6-81.1 mm Hg) to 135.2/74.1 mm Hg (95% CI, 134.2-136.2/73.2-75.0 mm Hg; P = .02/P < .001). Blood pressure control improved significantly more in absolute percentages between 1999-2000 and 2007-2008 vs 1988-1994 and 1999-2000 (18.6%; 95% CI, 13.3%-23.9%; vs 4.1%; 95% CI, -0.5% to 8.8%; P < .001). Better BP control reflected improvements in awareness (69.1%; 95% CI, 67.1%-71.1%; vs 80.7%; 95% CI, 78.1%-83.0%; P for trend = .03), treatment (54.0%; 95% CI, 52.0%-56.1%; vs 72.5%; 95% CI, 70.1%-74.8%; P = .004), and proportion of patients who were treated and had controlled hypertension (50.6%; 95% CI, 48.0%-53.2%; vs 69.1%; 95% CI, 65.7%-72.3%; P = .006). Hypertension control improved significantly between 1988-1994 and 2007-2008, across age, race, and sex groups, but was lower among individuals aged 18 to 39 years vs 40 to 59 years (P < .001) and 60 years or older (P < .001), and in Hispanic vs white individuals (P = .004). Conclusions: Blood pressure was controlled in an estimated 50.1% of all patients with hypertension in NHANES 2007-2008, with most of the improvement since 1988 occurring after 1999-2000. Hypertension control was significantly lower among younger than middle-aged individuals and older adults, and Hispanic vs white individuals.

JAMA: 26 May 2010; 303:2043-50
Egan BM, Zhao Y, Axon RN
JAMA: 26 May 2010; 303:2043-50 | PMID: 20501926
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Abstract

Trends in aortic valve replacement for elderly patients in the United States, 1999-2011.

Barreto-Filho JA, Wang Y, Dodson JA, Desai MM, ... Geirsson A, Krumholz HM
IMPORTANCE There is a need to describe contemporary outcomes of surgical aortic valve replacement (AVR) as the population ages and transcatheter options emerge. Objective To assess procedure rates and outcomes of surgical AVR over time. Design, setting, and participants A serial cross-sectional cohort study of 82 755 924 Medicare fee-for-service beneficiaries undergoing AVR in the United States between 1999 and 2011. MAIN OUTCOMES AND MEASURES Procedure rates for surgical AVR alone and with coronary artery bypass graft (CABG) surgery, 30-day and 1-year mortality, and 30-day readmission rates. RESULTS The AVR procedure rate increased by 19 (95% CI, 19-20) procedures per 100 000 person-years over the 12-year period (P&lt;.001), with an age-, sex-, and race-adjusted rate increase of 1.6% (95% CI, 1.0%-1.8%) per year. Mortality decreased at 30 days (absolute decrease, 3.4%; 95% CI, 3.0%-3.8%; adjusted annual decrease, 4.1%; 95% CI, 3.7%- 4.4%) per year and at 1 year (absolute decrease, 2.6%; 95% CI, 2.1%-3.2%; adjusted annual decrease, 2.5%; 95% CI, 2.3%-2.8%). Thirty-day all-cause readmission also decreased by 1.1% (95% CI, 0.9%-1.3%) per year. Aortic valve replacement with CABG surgery decreased, women and black patients had lower procedure and higher mortality rates, and mechanical prosethetic implants decreased, but 23.9% of patients 85 years and older continued to receive a mechanical prosthesis in 2011. CONCLUSIONS AND RELEVANCE Between 1999 and 2011, the rate of surgical AVR for elderly patients in the United States increased and outcomes improved substantially. Medicare data preclude the identification of the causes of the findings and the trends in procedure rates and outcomes cannot be causally linked. Nevertheless, the findings may be a useful benchmark for outcomes with surgical AVR for older patients eligible for surgery considering newer transcatheter treatments.

JAMA: 17 Nov 2013; 310:2078-85
Barreto-Filho JA, Wang Y, Dodson JA, Desai MM, ... Geirsson A, Krumholz HM
JAMA: 17 Nov 2013; 310:2078-85 | PMID: 24240935
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Abstract

Outcomes following transcatheter aortic valve replacement in the United States.

Mack MJ, Brennan JM, Brindis R, Carroll J, ... Holmes D, STS/ACC TVT Registry
IMPORTANCE Transcatheter aortic valve replacement (TAVR) was approved by the US Food and Drug Administration for the treatment of severe, symptomatic aortic stenosis and inoperable status (in 2011) and high-risk but operable status (starting in 2012). A national registry (the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy [STS/ACC TVT] Registry) was initiated to meet a condition for Medicare coverage and also facilitates outcome assessment and comparison with other trials and international registries. Objective To report the initial US commercial experience with TAVR. Design, setting, and participants We obtained results from all eligible US TAVR cases (n=7710) from 224 participating registry hospitals following the Edwards Sapien XT device commercialization (November 2011-May 2013). MAIN OUTCOMES AND MEASURES Primary outcomes included all-cause in-hospital mortality and stroke following TAVR. Secondary analyses included procedural complications and outcomes by clinical indication and access site. Device implantation success was defined as successful vascular access, deployment of a single device in the proper anatomic position, appropriate valve function without either moderate or severe AR, and successful retrieval of the delivery system. Thirty-day outcomes are presented for a representative 3133 cases (40.6%) at 114 centers with at least 80% complete follow-up reporting. RESULTS The 7710 patients who underwent TAVR included 1559 (20%) cases that were inoperable and 6151 (80%) cases that were high-risk but operable. The median age was 84 years (interquartile range [IQR], 78-88 years); 3783 patients (49%) were women and the median STS predicted risk of mortality was 7% (IQR, 5%-11%). At baseline, 2176 patients (75%) were either not at all satisfied (1297 patients [45%]) or mostly dissatisfied (879 patients [30%]) with their symptom status; 2198 (72%) had a 5-m walk time longer than 6 seconds (slow gait speed). The most common vascular access approach was transfemoral (4972 patients [64%]), followed by transapical (2197 patients [29%]) and other alternative approaches (536 patients [7%]); successful device implantation occurred in 7069 patients (92%; 95% CI, 91%-92%). The observed incidence of in-hospital mortality was 5.5% (95% CI, 5.0%-6.1%). Other major complications included stroke (2.0%; 95% CI, 1.7%-2.4%), dialysis-dependent renal failure (1.9%; 95% CI, 1.6%-2.2%), and major vascular injury (6.4%; 95% CI, 5.8%-6.9%). Median hospital stay was 6 days (IQR, 4-10 days), with 4613 (63%) discharged home. Among patients with available follow-up at 30 days (n=3133), the incidence of mortality was 7.6% (95% CI, 6.7%-8.6%) (noncardiovascular cause, 52%); a stroke had occurred in 2.8% (95% CI, 2.3%-3.5%), new dialysis in 2.5% (95% CI, 2.0%-3.1%), and reintervention in 0.5% (95% CI, 0.3%-0.8%). CONCLUSIONS AND RELEVANCE Among patients undergoing TAVR at US centers in the STS/ACC TVT Registry, device implantation success was achieved in 92% of cases, the overall in-hospital mortality rate was 5.5%, and the stroke rate was 2.0%. Although these postmarket US approval findings are comparable with prior published trial data and international experience, long-term follow-up is essential to assess continued efficacy and safety. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01737528.

JAMA: 17 Nov 2013; 310:2069-77
Mack MJ, Brennan JM, Brindis R, Carroll J, ... Holmes D, STS/ACC TVT Registry
JAMA: 17 Nov 2013; 310:2069-77 | PMID: 24240934
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Abstract

Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome: The VISTA-16 Randomized Clinical Trial.

Nicholls SJ, Kastelein JJ, Schwartz GG, Bash D, ... Nissen SE, for the VISTA-16 Investigators
IMPORTANCE Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. Objective To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. Design, setting, and participants A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130246.

JAMA: 18 Nov 2013; epub ahead of print
Nicholls SJ, Kastelein JJ, Schwartz GG, Bash D, ... Nissen SE, for the VISTA-16 Investigators
JAMA: 18 Nov 2013; epub ahead of print | PMID: 24247616
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Abstract

Transendocardial Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells for Ischemic Cardiomyopathy: The TAC-HFT Randomized Trial.

Heldman AW, Difede DL, Fishman JE, Zambrano JP, ... Mendizabal A, Hare JM
IMPORTANCE Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. Objective To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. Design, setting, and patients A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00768066.

JAMA: 18 Nov 2013; epub ahead of print
Heldman AW, Difede DL, Fishman JE, Zambrano JP, ... Mendizabal A, Hare JM
JAMA: 18 Nov 2013; epub ahead of print | PMID: 24247587
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Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction: The ROSE Acute Heart Failure Randomized Trial.

Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, ... Redfield MM, for the NHLBI Heart Failure Clinical Research Network
IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. Objective To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. Design, setting, and participants Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.

JAMA: 18 Nov 2013; epub ahead of print
Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, ... Redfield MM, for the NHLBI Heart Failure Clinical Research Network
JAMA: 18 Nov 2013; epub ahead of print | PMID: 24247300
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Abstract

Long-term Drug Treatment for Obesity: A Systematic and Clinical Review.

Yanovski SZ, Yanovski JA
IMPORTANCE Thirty-six percent of US adults are obese, and many cannot lose sufficient weight to improve health with lifestyle interventions alone. Objective To conduct a systematic review of medications currently approved in the United States for obesity treatment in adults. We also discuss off-label use of medications studied for obesity and provide considerations for obesity medication use in clinical practice. EVIDENCE REVIEW A PubMed search from inception through September 2013 was performed to find meta-analyses, systematic reviews, and randomized, placebo-controlled trials for currently approved obesity medications lasting at least 1 year that had a primary or secondary outcome of body weight change, included at least 50 participants per group, reported at least 50% retention, and reported results on an intention-to-treat basis. Studies of medications approved for other purposes but tested for obesity treatment were also reviewed. FINDINGS Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate-extended release at 1 year. The proportion of patients achieving clinically meaningful (at least 5%) weight loss ranges from 37% to 47% for lorcaserin, 35% to 73% for orlistat, and 67% to 70% for top-dose phentermine plus topiramate-extended release. All 3 medications produce greater improvements in many cardiometabolic risk factors than placebo, but no obesity medication has been shown to reduce cardiovascular morbidity or mortality. Most prescriptions are for noradrenergic medications, despite their approval only for short-term use and limited data for their long-term safety and efficacy. CONCLUSIONS AND RELEVANCE Medications approved for long-term obesity treatment, when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo. By discontinuing medication in patients who do not respond with weight loss of at least 5%, clinicians can decrease their patients\' exposure to the risks and costs of drug treatment when there is little prospect of long-term benefit.

JAMA: 14 Nov 2013; epub ahead of print
Yanovski SZ, Yanovski JA
JAMA: 14 Nov 2013; epub ahead of print | PMID: 24231879
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Abstract

Self-management Counseling in Patients With Heart Failure: The Heart Failure Adherence and Retention Randomized Behavioral Trial.

Powell LH, Calvin JE, Richardson D, Janssen I, ... Avery E, for the HART Investigators
Context: Motivating patients with heart failure to adhere to medical advice has not translated into clinical benefit, but past trials have had methodological limitations. Objective: To determine the value of self-management counseling plus heart failure education, compared with heart failure education alone, for the primary end point of death or heart failure hospitalization. Design, Setting, and PATIENTS: The Heart Failure Adherence and Retention Trial (HART), a single-center, multiple-hospital, partially blinded behavioral efficacy randomized controlled trial involving 902 patients with mild to moderate heart failure and reduced or preserved systolic function, randomized from the Chicago metropolitan area between October 2001 and October 2004 and undergoing follow-up for 2 to 3 subsequent years. Interventions: All patients were offered 18 contacts and 18 heart failure educational tip sheets during the course of 1 year. Patients randomized to the education group received tip sheets in the mail and telephone calls to check comprehension. Patients randomized to the self-management group received tip sheets in groups and were taught self-management skills to implement the advice. Main outcome measure: Death or heart failure hospitalization during a median of 2.56 years of follow-up. Results: Patients were representative of typical clinical populations (mean age, 63.6 years; 47% women, 40% racial/ethnic minority, 52% with annual family income less than $30 000, and 23% with preserved systolic function). The rate of the primary end point in the self-management group was no different from that in the education group (163 [40.1%)] vs 171 [41.2%], respectively; odds ratio, 0.95 [95% confidence interval, 0.72-1.26]). There were no significant differences on any secondary end points, including death, heart failure hospitalization, all-cause hospitalization, or quality of life. Conclusions: Compared with an enhanced educational intervention alone, the addition of self-management counseling did not reduce death or heart failure hospitalization in patients with mild to moderate heart failure. Trial registration  clinicaltrials.gov Identifier: NCT00018005.

JAMA: 22 Sep 2010; 304:1331-1338
Powell LH, Calvin JE, Richardson D, Janssen I, ... Avery E, for the HART Investigators
JAMA: 22 Sep 2010; 304:1331-1338 | PMID: 20858878
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Abstract

High-flow oxygen for treatment of cluster headache: a randomized trial.

Cohen AS, Burns B, Goadsby PJ
Context: Cluster headache is an excruciatingly painful primary headache syndrome, with attacks of unilateral pain and cranial autonomic symptoms. The current licensed treatment for acute attacks is subcutaneous sumatriptan. Objective: To ascertain whether high-flow inhaled oxygen was superior to placebo in the acute treatment of cluster headache. Design, setting, and patients: A double-blind, randomized, placebo-controlled crossover trial of 109 adults (aged 18-70 years) with cluster headache as defined by the International Headache Society. Patients treated 4 headache episodes with high-flow inhaled oxygen or placebo, alternately. Patients were randomized to the order in which they received the active treatment or placebo. Patients were recruited and followed up between 2002 and 2007 at the National Hospital for Neurology and Neurosurgery, London, England. Intervention: Inhaled oxygen at 100%, 12 L/min, delivered by face mask, for 15 minutes at the start of an attack of cluster headache or high-flow air placebo delivered alternately for 4 attacks. Main outcome measures: The primary end point was to render the patient pain free, or in the absence of a diary to have adequate relief, at 15 minutes. Secondary end points included rendering the patient pain free at 30 minutes, reduction in pain up to 60 minutes, need for rescue medication 15 minutes after treatment, overall response to the treatment and overall functional disability, and effect on associated symptoms. Results: Fifty-seven patients with episodic cluster headache and 19 with chronic cluster headache were available for the analysis. For the primary end point the difference between oxygen, 78% (95% confidence interval, 71%-85% for 150 attacks) and air, 20% (95% confidence interval, 14%-26%; for 148 attacks) was significant (Wald test, chi(5)(2) = 66.7, P < .001). There were no important adverse events. Conclusion: Treatment of patients with cluster headache at symptom onset using inhaled high-flow oxygen compared with placebo was more likely to result in being pain-free at 15 minutes. Trial registration: isrctn.org Identifier: ISRCTN94092997.

JAMA: 09 Dec 2009; 302:2451-7
Cohen AS, Burns B, Goadsby PJ
JAMA: 09 Dec 2009; 302:2451-7 | PMID: 19996400
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Abstract

Association Between 9p21 Genomic Markers and Heart Disease: A Meta-analysis.

Palomaki GE, Melillo S, Bradley LA
Context: Associations between chromosome 9p21 single-nucleotide polymorphisms (SNPs) and heart disease have been reported and replicated. If testing improves risk assessments using traditional factors, it may provide opportunities to improve public health. ObjectiveS: To perform a targeted systematic review of published literature for effect size, heterogeneity, publication bias, and strength of evidence and to consider whether testing might provide clinical utility. Data sources: Electronic search via HuGE Navigator through January 2009 and review of reference lists from included articles. Study selection: English-language articles that tested for 9p21 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an odds ratio (OR). Articles were excluded if reporting only intermediate outcomes (eg, atherosclerosis) or if all participants had existing disease. Twenty-five articles were initially identified and 16 were included. A follow-up search identified 6 additional articles. Data extraction: Independent extraction was performed by 2 reviewers and consensus was reached. Credibility of evidence was assessed using published Venice criteria. Data synthesis: Forty-seven distinct data sets from the 22 articles were analyzed, including 35 872 cases and 95 837 controls. The summary OR for heart disease among individuals with 2 vs 1 at-risk alleles was 1.25 (95% confidence interval [CI], 1.21-1.29), with low to moderate heterogeneity. Age at disease diagnosis was a significant covariate, with ORs of 1.35 (95% CI, 1.30-1.40) for age 55 years or younger and 1.21 (95% CI, 1.16-1.25) for age 75 years or younger. For a 65-year-old man, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 13.2% vs 11%. For a 40-year-old woman, the 10-year heart disease risk for 2 vs 1 at-risk alleles would be 2.4% vs 2.0%. Nearly identical but inverse results were found when comparing 1 vs 0 at-risk alleles. Three studies showed net reclassification indexes ranging from -0.1% to 4.8%. Conclusion: We found a statistically significant association between 9p21 SNPs and heart disease that varied by age at disease onset, but the magnitude of the association was small.

JAMA: 17 Feb 2010; 303:648-56
Palomaki GE, Melillo S, Bradley LA
JAMA: 17 Feb 2010; 303:648-56 | PMID: 20159873
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Abstract

Validation of the Atherosclerotic Cardiovascular Disease Pooled Cohort Risk Equations.

Muntner P, Colantonio LD, Cushman M, Goff DC, ... Lloyd-Jones DM, Safford MM
IMPORTANCE The American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort risk equations were developed to estimate atherosclerotic cardiovascular disease (CVD) risk and guide statin initiation. Objective To assess calibration and discrimination of the Pooled Cohort risk equations in a contemporary US population. Design, setting, and participants Adults aged 45 to 79 years enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between January 2003 and October 2007 and followed up through December 2010. We studied participants for whom atherosclerotic CVD risk may trigger a discussion of statin initiation (those without clinical atherosclerotic CVD or diabetes, low-density lipoprotein cholesterol level between 70 and 189 mg/dL, and not taking statins; n = 10 997). MAIN OUTCOMES AND MEASURES Predicted risk and observed adjudicated atherosclerotic CVD incidence (nonfatal myocardial infarction, coronary heart disease [CHD] death, nonfatal or fatal stroke) at 5 years because REGARDS participants have not been followed up for 10 years. Additional analyses, limited to Medicare beneficiaries (n = 3333), added atherosclerotic CVD events identified in Medicare claims data. RESULTS There were 338 adjudicated events (192 CHD events, 146 strokes). The observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a 10-year predicted atherosclerotic CVD risk of less than 5% was 1.9 (95% CI, 1.3-2.7) and 1.9, respectively, risk of 5% to less than 7.5% was 4.8 (95% CI, 3.4-6.7) and 4.8, risk of 7.5% to less than 10% was 6.1 (95% CI, 4.4-8.6) and 6.9, and risk of 10% or greater was 12.0 (95% CI, 10.6-13.6) and 15.1 (Hosmer-Lemeshow χ2 = 19.9, P = .01). The C index was 0.72 (95% CI, 0.70-0.75). There were 234 atherosclerotic CVD events (120 CHD events, 114 strokes) among Medicare-linked participants and the observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a predicted risk of less than 7.5% was 5.3 (95% CI, 2.8-10.1) and 4.0, respectively, risk of 7.5% to less than 10% was 7.9 (95% CI, 4.6-13.5) and 6.4, and risk of 10% or greater was 17.4 (95% CI, 15.3-19.8) and 16.4 (Hosmer-Lemeshow χ2 = 5.4, P = .71). The C index was 0.67 (95% CI, 0.64-0.71). CONCLUSIONS AND RELEVANCE In this cohort of US adults for whom statin initiation is considered based on the ACC/AHA Pooled Cohort risk equations, observed and predicted 5-year atherosclerotic CVD risks were similar, indicating that these risk equations were well calibrated in the population for which they were designed to be used, and demonstrated moderate to good discrimination.

JAMA: 30 Mar 2014; epub ahead of print
Muntner P, Colantonio LD, Cushman M, Goff DC, ... Lloyd-Jones DM, Safford MM
JAMA: 30 Mar 2014; epub ahead of print | PMID: 24682252
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Abstract

Resistant hypertension: a review of diagnosis and management.

Vongpatanasin W
Resistant hypertension-uncontrolled hypertension with 3 or more antihypertensive agents-is increasingly common in clinical practice. Clinicians should exclude pseudoresistant hypertension, which results from nonadherence to medications or from elevated blood pressure related to the white coat syndrome. In patients with truly resistant hypertension, thiazide diuretics, particularly chlorthalidone, should be considered as one of the initial agents. The other 2 agents should include calcium channel blockers and angiotensin-converting enzyme inhibitors for cardiovascular protection. An increasing body of evidence has suggested benefits of mineralocorticoid receptor antagonists, such as eplerenone and spironolactone, in improving blood pressure control in patients with resistant hypertension, regardless of circulating aldosterone levels. Thus, this class of drugs should be considered for patients whose blood pressure remains elevated after treatment with a 3-drug regimen to maximal or near maximal doses. Resistant hypertension may be associated with secondary causes of hypertension including obstructive sleep apnea or primary aldosteronism. Treating these disorders can significantly improve blood pressure beyond medical therapy alone. The role of device therapy for treating the typical patient with resistant hypertension remains unclear.

JAMA: 03 Jun 2014; 311:2216-24
Vongpatanasin W
JAMA: 03 Jun 2014; 311:2216-24 | PMID: 24893089
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Abstract

Relationship between early physician follow-up and 30-day readmission among Medicare beneficiaries hospitalized for heart failure.

Hernandez AF, Greiner MA, Fonarow GC, Hammill BG, ... Peterson ED, Curtis LH
Context: Readmission after hospitalization for heart failure is common. Early outpatient follow-up after hospitalization has been proposed as a means of reducing readmission rates. However, there are limited data describing patterns of follow-up after heart failure hospitalization and its association with readmission rates. Objective: To examine associations between outpatient follow-up within 7 days after discharge from a heart failure hospitalization and readmission within 30 days. Design, setting, and patients: Observational analysis of patients 65 years or older with heart failure and discharged to home from hospitals participating in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure and the Get With the Guidelines-Heart Failure quality improvement program from January 1, 2003, through December 31, 2006. Main outcome measure: All-cause readmission within 30 days after discharge. Results: The study population included 30,136 patients from 225 hospitals. Median length of stay was 4 days (interquartile range, 2-6) and 21.3% of patients were readmitted within 30 days. At the hospital level, the median percentage of patients who had early follow-up after discharge from the index hospitalization was 38.3% (interquartile range, 32.4%-44.5%). Compared with patients whose index admission was in a hospital in the lowest quartile of early follow-up (30-day readmission rate, 23.3%), the rates of 30-day readmission were 20.5% among patients in the second quartile (risk-adjusted hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78-0.93), 20.5% among patients in the third quartile (risk-adjusted HR, 0.87; 95% CI, 0.78-0.96), and 20.9% among patients in the fourth quartile (risk-adjusted HR, 0.91; 95% CI, 0.83-1.00). Conclusions: Among patients who are hospitalized for heart failure, substantial variation exists in hospital-level rates of early outpatient follow-up after discharge. Patients who are discharged from hospitals that have higher early follow-up rates have a lower risk of 30-day readmission. Trial registration: clinicaltrials.gov Identifier: NCT00344513.

JAMA: 05 May 2010; 303:1716-22
Hernandez AF, Greiner MA, Fonarow GC, Hammill BG, ... Peterson ED, Curtis LH
JAMA: 05 May 2010; 303:1716-22 | PMID: 20442387
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Abstract

Effect of Aleglitazar on Cardiovascular Outcomes After Acute Coronary Syndrome in Patients With Type 2 Diabetes Mellitus: The AleCardio Randomized Clinical Trial.

Lincoff AM, Tardif JC, Schwartz GG, Nicholls SJ, ... Grobbee DE, for the AleCardio Investigators
IMPORTANCE No therapy directed against diabetes has been shown to unequivocally reduce the excess risk of cardiovascular complications. Aleglitazar is a dual agonist of peroxisome proliferator-activated receptors with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles. Objective To determine whether the addition of aleglitazar to standard medical therapy reduces cardiovascular morbidity and mortality among patients with type 2 diabetes mellitus and a recent acute coronary syndrome (ACS). Design, setting, and participants AleCardio was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial conducted in 720 hospitals in 26 countries throughout North America, Latin America, Europe, and Asia-Pacific regions. The enrollment of 7226 patients hospitalized for ACS (myocardial infarction or unstable angina) with type 2 diabetes occurred between February 2010 and May 2012; treatment was planned to continue until patients were followed-up for at least 2.5 years and 950 primary end point events were positively adjudicated. INTERVENTIONS Randomized in a 1:1 ratio to receive aleglitazar 150 µg or placebo daily. MAIN OUTCOMES AND MEASURES The primary efficacy end point was time to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Principal safety end points were hospitalization due to heart failure and changes in renal function. RESULTS The trial was terminated on July 2, 2013, after a median follow-up of 104 weeks, upon recommendation of the data and safety monitoring board due to futility for efficacy at an unplanned interim analysis and increased rates of safety end points. A total of 3.1% of patients were lost to follow-up and 3.2% of patients withdrew consent. The primary end point occurred in 344 patients (9.5%) in the aleglitazar group and 360 patients (10.0%) in the placebo group (hazard ratio, 0.96 [95% CI, 0.83-1.11]; P = .57). Rates of serious adverse events, including heart failure (3.4% for aleglitazar vs 2.8% for placebo, P = .14), gastrointestinal hemorrhages (2.4% for aleglitazar vs 1.7% for placebo, P = .03), and renal dysfunction (7.4% for aleglitazar vs 2.7% for placebo, P &lt; .001) were increased. CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes and recent ACS, use of aleglitazar did not reduce the risk of cardiovascular outcomes. These findings do not support the use of aleglitazar in this setting with a goal of reducing cardiovascular risk. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01042769.

JAMA: 30 Mar 2014; epub ahead of print
Lincoff AM, Tardif JC, Schwartz GG, Nicholls SJ, ... Grobbee DE, for the AleCardio Investigators
JAMA: 30 Mar 2014; epub ahead of print | PMID: 24682069
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Abstract

Comparison of Balloon-Expandable vs Self-expandable Valves in Patients Undergoing Transcatheter Aortic Valve Replacement: The CHOICE Randomized Clinical Trial.

Abdel-Wahab M, Mehilli J, Frerker C, Neumann FJ, ... Richardt G, for the CHOICE investigators
IMPORTANCE Transcatheter aortic valve replacement (TAVR) is an effective treatment option for high-risk patients with severe aortic stenosis. Different from surgery, transcatheter deployment of valves requires either a balloon-expandable or self-expandable system. A randomized comparison of these 2 systems has not been performed. Objective To determine whether the balloon-expandable device is associated with a better success rate than the self-expandable device. Design, setting, and patients The CHOICE study was an investigator-initiated trial in high-risk patients with severe aortic stenosis and an anatomy suitable for the transfemoral TAVR procedure. One hundred twenty-one patients were randomly assigned to receive a balloon-expandable valve (Edwards Sapien XT) and 120 were assigned to receive a self-expandable valve (Medtronic CoreValve). Patients were enrolled between March 2012 and December 2013 at 5 centers in Germany. INTERVENTIONS Transfemoral TAVR with a balloon-expandable or self-expandable device. MAIN OUTCOMES AND MEASURES The primary end point was device success, which is a composite end point including successful vascular access and deployment of the device and retrieval of the delivery system, correct position of the device, intended performance of the heart valve without moderate or severe regurgitation, and only 1 valve implanted in the proper anatomical location. Secondary end points included cardiovascular mortality, bleeding and vascular complications, postprocedural pacemaker placement, and a combined safety end point at 30 days, including all-cause mortality, major stroke, and other serious complications. RESULTS Device success occurred in 116 of 121 patients (95.9%) in the balloon-expandable valve group and 93 of 120 patients (77.5%) in the self-expandable valve group (relative risk [RR], 1.24, 95% CI, 1.12-1.37, P &lt; .001). This was attributed to a significantly lower frequency of residual more-than-mild aortic regurgitation (4.1% vs 18.3%; RR, 0.23; 95% CI, 0.09-0.58; P &lt; .001) and the less frequent need for implanting more than 1 valve (0.8% vs 5.8%, P = .03) in the balloon-expandable valve group. Cardiovascular mortality at 30 days was 4.1% in the balloon-expandable valve group and 4.3% in the self-expandable valve group (RR, 0.97; 95% CI, 0.29-3.25; P = .99). Bleeding and vascular complications were not significantly different, and the combined safety end point occurred in 18.2% of those in the balloon-expandable valve group and 23.1% of the self-expandable valve group (RR, 0.79; 95% CI, 0.48-1.30; P = .42). Placement of a new permanent pacemaker was less frequent in the balloon-expandable valve group (17.3% vs 37.6%, P = .001). CONCLUSIONS AND RELEVANCE Among patients with high-risk aortic stenosis undergoing TAVR, the use of a balloon-expandable valve resulted in a greater rate of device success than use of a self-expandable valve. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01645202.

JAMA: 30 Mar 2014; epub ahead of print
Abdel-Wahab M, Mehilli J, Frerker C, Neumann FJ, ... Richardt G, for the CHOICE investigators
JAMA: 30 Mar 2014; epub ahead of print | PMID: 24682026
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Abstract

Risk of Major Adverse Cardiac Events Following Noncardiac Surgery in Patients With Coronary Stents.

Hawn MT, Graham LA, Richman JS, Itani KM, Henderson WG, Maddox TM
IMPORTANCE Guidelines recommend delaying noncardiac surgery in patients after coronary stent procedures for 1 year after drug-eluting stents (DES) and for 6 weeks after bare metal stents (BMS). The evidence underlying these recommendations is limited and conflicting. Objective To determine risk factors for adverse cardiac events in patients undergoing noncardiac surgery following coronary stent implantation. Design, setting, and participants A national, retrospective cohort study of 41 989 Veterans Affairs (VA) and non-VA operations occurring in the 24 months after a coronary stent implantation between 2000 and 2010. Nonlinear generalized additive models examined the association between timing of surgery and stent type with major adverse cardiac events (MACE) adjusting for patient, surgery, and cardiac risk factors. A nested case-control study assessed the association between perioperative antiplatelet cessation and MACE. MAIN OUTCOMES AND MEASURES A composite 30-day MACE rate of all-cause mortality, myocardial infarction, and cardiac revascularization. RESULTS Within 24 months of 124 844 coronary stent implantations (47.6% DES, 52.4% BMS), 28 029 patients (22.5%; 95% CI, 22.2%-22.7%) underwent noncardiac operations resulting in 1980 MACE (4.7%; 95% CI, 4.5%-4.9%). Time between stent and surgery was associated with MACE (&lt;6 weeks, 11.6%; 6 weeks to &lt;6 months, 6.4%; 6-12 months, 4.2%; &gt;12-24 months, 3.5%; P &lt; .001). MACE rate by stent type was 5.1% for BMS and 4.3% for DES (P &lt; .001). After adjustment, the 3 factors most strongly associated with MACE were nonelective surgical admission (adjusted odds ratio [AOR], 4.77; 95% CI, 4.07-5.59), history of myocardial infarction in the 6 months preceding surgery (AOR, 2.63; 95% CI, 2.32-2.98), and revised cardiac risk index greater than 2 (AOR, 2.13; 95% CI, 1.85-2.44). Of the 12 variables in the model, timing of surgery ranked fifth in explanatory importance measured by partial effects analysis. Stent type ranked last, and DES was not significantly associated with MACE (AOR, 0.91; 95% CI, 0.83-1.01). After both BMS and DES placement, the risk of MACE was stable at 6 months. A case-control analysis of 284 matched pairs found no association between antiplatelet cessation and MACE (OR, 0.86; 95% CI, 0.57-1.29). CONCLUSIONS AND RELEVANCE Among patients undergoing noncardiac surgery within 2 years of coronary stent placement, MACE were associated with emergency surgery and advanced cardiac disease but not stent type or timing of surgery beyond 6 months after stent implantation. Guideline emphasis on stent type and surgical timing for both DES and BMS should be reevaluated.

JAMA: 08 Oct 2013; 310:1462-1472
Hawn MT, Graham LA, Richman JS, Itani KM, Henderson WG, Maddox TM
JAMA: 08 Oct 2013; 310:1462-1472 | PMID: 24101118
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Abstract

Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest: A Randomized Clinical Trial.

Kim F, Nichol G, Maynard C, Hallstrom A, ... Olsufka M, Cobb LA
IMPORTANCE Hospital cooling improves outcome after cardiac arrest, but prehospital cooling immediately after return of spontaneous circulation may result in better outcomes. Objective To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF. Design, setting, and participants A randomized clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, 2012. Patient follow-up was completed by May 1, 2013. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomization. MAIN OUTCOMES AND MEASURES The primary outcomes were survival to hospital discharge and neurological status at discharge. RESULTS The intervention decreased mean core temperature by 1.20°C (95% CI, -1.33°C to -1.07°C) in patients with VF and by 1.30°C (95% CI, -1.40°C to -1.20°C) in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34°C by about 1 hour compared with the control group. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% [95% CI, 57.0%-68.0%] vs 64.3% [95% CI, 58.6%-69.5%], respectively; P = .69) and among patients without VF (19.2% [95% CI, 15.6%-23.4%] vs 16.3% [95% CI, 12.9%-20.4%], respectively; P = .30). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% [95% CI, 51.8%-63.1%] of cases had full recovery or mild impairment vs 61.9% [95% CI, 56.2%-67.2%] of controls; P = .69) or those without VF (14.4% [95% CI, 11.3%-18.2%] of cases vs 13.4% [95% CI,10.4%-17.2%] of controls; P = .30). Overall, the intervention group experienced rearrest in the field more than the control group (26% [95% CI, 22%-29%] vs 21% [95% CI, 18%-24%], respectively; P = .008), as well as increased diuretic use and pulmonary edema on first chest x-ray, which resolved within 24 hours after admission. CONCLUSION AND RELEVANCE Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00391469.

JAMA: 17 Nov 2013; epub ahead of print
Kim F, Nichol G, Maynard C, Hallstrom A, ... Olsufka M, Cobb LA
JAMA: 17 Nov 2013; epub ahead of print | PMID: 24240712
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Abstract

Association of Coronary CT Angiography or Stress Testing With Subsequent Utilization and Spending Among Medicare Beneficiaries.

Shreibati JB, Baker LC, Hlatky MA
Context Coronary computed tomography angiography (CCTA) is a new noninvasive diagnostic test for coronary artery disease (CAD), but its association with subsequent clinical management has not been established. Objective To compare utilization and spending associated with functional (stress testing) and anatomical (CCTA) noninvasive cardiac testing in a Medicare population. Design, Setting, and Patients Retrospective, observational cohort study using claims data from a 20% random sample of 2005-2008 Medicare fee-for-service beneficiaries 66 years or older with no claims for CAD in the preceding year, who received nonemergent, noninvasive testing for CAD (n = 282 830). Main Outcome Measures Cardiac catheterization, coronary revascularization, acute myocardial infarction, all-cause mortality, and total and CAD-related Medicare spending over 180 days of follow-up. Results Compared with stress myocardial perfusion scintigraphy (MPS), CCTA was associated with an increased likelihood of subsequent cardiac catheterization (22.9% vs 12.1%; adjusted odds ratio [AOR], 2.19 [95% CI, 2.08 to 2.32]; P < .001), percutaneous coronary intervention (7.8% vs 3.4%; AOR, 2.49 [2.28 to 2.72]; P < .001), and coronary artery bypass graft surgery (3.7% vs 1.3%; AOR, 3.00 [2.63 to 3.41]; P < .001). CCTA was also associated with higher total health care spending ($4200 [$3193 to $5267]; P < .001), which was almost entirely attributable to payments for any claims for CAD ($4007 [$3256 to $4835]; P < .001). Compared with MPS, there was lower associated spending with stress echocardiography (-$4981 [-$4991 to -$4969]; P < .001) and exercise electrocardiography (-$7449 [-$7452 to -$7444]; P < .001). At 180 days, CCTA was associated with a similar likelihood of all-cause mortality (1.05% vs 1.28%; AOR, 1.11 [0.88 to 1.38]; P = .32) and a slightly lower likelihood of hospitalization for acute myocardial infarction (0.19% vs 0.43%; AOR, 0.60 [0.37 to 0.98]; P = .04). Conclusion Medicare beneficiaries who underwent CCTA in a nonacute setting were more likely to undergo subsequent invasive cardiac procedures and have higher CAD-related spending than patients who underwent stress testing.

JAMA: 17 Nov 2011; 306:2128-2136
Shreibati JB, Baker LC, Hlatky MA
JAMA: 17 Nov 2011; 306:2128-2136 | PMID: 22089720
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Kidney Function After Off-Pump or On-Pump Coronary Artery Bypass Graft Surgery: A Randomized Clinical Trial.

Garg AX, Devereaux PJ, Yusuf S, Cuerden MS, ... Lamy A, for the CORONARY Investigators
IMPORTANCE Most acute kidney injury observed in the hospital is defined by sudden mild or moderate increases in the serum creatinine concentration, which may persist for several days. Such acute kidney injury is associated with lower long-term kidney function. However, it has not been demonstrated that an intervention that reduces the risk of such acute kidney injury better preserves long-term kidney function. ObjectiveS To characterize the risk of acute kidney injury with an intervention in a randomized clinical trial and to determine if there is a difference between the 2 treatment groups in kidney function 1 year later. Design, setting, and participants The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) enrolled 4752 patients undergoing first isolated coronary artery bypass graft (CABG) surgery at 79 sites in 19 countries. Patients were randomized to receive CABG surgery either with a beating-heart technique (off-pump) or with cardiopulmonary bypass (on-pump). From January 2010 to November 2011, 2932 patients (from 63 sites in 16 countries) from CORONARY were enrolled into a kidney function substudy to record serum creatinine concentrations during the postoperative period and at 1 year. The last 1-year serum creatinine concentration was recorded on January 18, 2013. MAIN OUTCOMES AND MEASURES Acute kidney injury within 30 days of surgery (≥50% increase in serum creatinine concentration from prerandomization concentration) and loss of kidney function at 1 year (≥20% loss in estimated glomerular filtration rate from prerandomization level). RESULTS Off-pump (n = 1472) vs on-pump (n = 1460) CABG surgery reduced the risk of acute kidney injury (17.5% vs 20.8%, respectively; relative risk, 0.83 [95% CI, 0.72-0.97], P = .01); however, there was no significant difference between the 2 groups in the loss of kidney function at 1 year (17.1% vs 15.3%, respectively; relative risk, 1.10 [95% CI, 0.95-1.29], P = .23). Results were consistent with multiple alternate continuous and categorical definitions of acute kidney injury or kidney function loss, and in the subgroup with baseline chronic kidney disease. CONCLUSIONS AND RELEVANCE Use of off-pump compared with on-pump CABG surgery reduced the risk of postoperative acute kidney injury, without evidence of better preserved kidney function with off-pump CABG surgery at 1 year. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00463294.

JAMA: 02 Jun 2014; 311:2191-2198
Garg AX, Devereaux PJ, Yusuf S, Cuerden MS, ... Lamy A, for the CORONARY Investigators
JAMA: 02 Jun 2014; 311:2191-2198 | PMID: 24886787
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Abstract

Comparison of Application of the ACC/AHA Guidelines, Adult Treatment Panel III Guidelines, and European Society of Cardiology Guidelines for Cardiovascular Disease Prevention in a European Cohort.

Kavousi M, Leening MJ, Nanchen D, Greenland P, ... Hofman A, Franco OH
IMPORTANCE The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines introduced a prediction model and lowered the threshold for treatment with statins to a 7.5% 10-year hard atherosclerotic cardiovascular disease (ASCVD) risk. Implications of the new guideline\'s threshold and model have not been addressed in non-US populations or compared with previous guidelines. Objective To determine population-wide implications of the ACC/AHA, the Adult Treatment Panel III (ATP-III), and the European Society of Cardiology (ESC) guidelines using a cohort of Dutch individuals aged 55 years or older. Design, setting, and participants We included 4854 Rotterdam Study participants recruited in 1997-2001. We calculated 10-year risks for "hard" ASCVD events (including fatal and nonfatal coronary heart disease [CHD] and stroke) (ACC/AHA), hard CHD events (fatal and nonfatal myocardial infarction, CHD mortality) (ATP-III), and atherosclerotic CVD mortality (ESC). MAIN OUTCOMES AND MEASURES Events were assessed until January 1, 2012. Per guideline, we calculated proportions of individuals for whom statins would be recommended and determined calibration and discrimination of risk models. RESULTS The mean age was 65.5 (SD, 5.2) years. Statins would be recommended for 96.4% (95% CI, 95.4%-97.1%; n = 1825) of men and 65.8% (95% CI, 63.8%-67.7%; n = 1523) of women by the ACC/AHA, 52.0% (95% CI, 49.8%-54.3%; n = 985) of men and 35.5% (95% CI, 33.5%-37.5%; n = 821) of women by the ATP-III, and 66.1% (95% CI, 64.0%-68.3%; n = 1253) of men and 39.1% (95% CI, 37.1%-41.2%; n = 906) of women by ESC guidelines. With the ACC/AHA model, average predicted risk vs observed cumulative incidence of hard ASCVD events was 21.5% (95% CI, 20.9%-22.1%) vs 12.7% (95% CI, 11.1%-14.5%) for men (192 events) and 11.6% (95% CI, 11.2%-12.0%) vs 7.9% (95% CI, 6.7%-9.2%) for women (151 events). Similar overestimation occurred with the ATP-III model (98 events in men and 62 events in women) and ESC model (50 events in men and 37 events in women). The C statistic was 0.67 (95% CI, 0.63-0.71) in men and 0.68 (95% CI, 0.64-0.73) in women for hard ASCVD (ACC/AHA), 0.67 (95% CI, 0.62-0.72) in men and 0.69 (95% CI, 0.63-0.75) in women for hard CHD (ATP-III), and 0.76 (95% CI, 0.70-0.82) in men and 0.77 (95% CI, 0.71-0.83) in women for CVD mortality (ESC). CONCLUSIONS AND RELEVANCE In this European population aged 55 years or older, proportions of individuals eligible for statins differed substantially among the guidelines. The ACC/AHA guideline would recommend statins for nearly all men and two-thirds of women, proportions exceeding those with the ATP-III or ESC guidelines. All 3 risk models provided poor calibration and moderate to good discrimination. Improving risk predictions and setting appropriate population-wide thresholds are necessary to facilitate better clinical decision making.

JAMA: 30 Mar 2014; epub ahead of print
Kavousi M, Leening MJ, Nanchen D, Greenland P, ... Hofman A, Franco OH
JAMA: 30 Mar 2014; epub ahead of print | PMID: 24681960
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Temporal Onset, Risk Factors, and Outcomes Associated With Stroke After Coronary Artery Bypass Grafting.

Tarakji KG, Sabik JF, Bhudia SK, Batizy LH, Blackstone EH
Context Stroke is a devastating and potentially preventable complication of coronary artery bypass graft (CABG) surgery. Better understanding of the timing and risk factors for stroke associated with CABG are needed. Objectives To investigate temporal trends in stroke after CABG and to identify stroke risk factors and association with longitudinal outcomes. Design, Setting, and Patients Prospective study conducted from 1982 through 2009 at a single US academic medical center among 45 432 consecutive patients (mean age, 63 [SD, 10] years) undergoing isolated primary or reoperative CABG surgery. Strokes occurring following CABG were recorded prospectively and classified as having occurred intraoperatively or postoperatively. Complications and survival after stroke were assessed in propensity-matched groups. Intervention CABG performed using 4 different operative strategies (off-pump, on-pump with beating heart, on-pump with arrested heart, on-pump with hypothermic circulatory arrest). Main Outcome Measures Hospital complications; late survival. Results Among 45 432 patients undergoing CABG surgery, 705 (1.6% [95% confidence interval {CI}, 1.4%-1.7%]) experienced a stroke. The prevalence of stroke peaked in 1988 at 2.6% (95% CI, 1.9%-3.4%), then declined at 4.69% (95% CI, 4.68%-4.70%) per year (P = .04), despite increasing patient comorbidity. Overall, 279 strokes (40%) occurred intraoperatively and 409 (58%) occurred postoperatively (timing indeterminate in 17 patients). Postoperative stroke peaked at 40 hours, decreasing to 0.055%/d (95% CI, 0.047%-0.065%) by day 6. Risk factors for both intraoperative and postoperative stroke included older age (odds ratio, 8.5 [95% CI, 3.2-22]) and variables representing arteriosclerotic burden. Intraoperative stroke rates were lowest in off-pump CABG (0.14% [95% CI, 0.029%-0.40%]) and on-pump beating-heart CABG (0% [95% CI, 0%-1.6%]), intermediate with on-pump arrested-heart CABG (0.50% [95% CI, 0.41%-0.61%]), and highest with on-pump CABG with hypothermic circulatory arrest (5.3% [95% CI, 2.0%-11%]). Patients with stroke had worse adjusted hospital outcomes, longer intensive care and postoperative stays, and worse downstream survival (mean, 11 [SD, 8.6] years). Conclusion Among patients undergoing CABG surgery at a single center over the past 30 years, the occurrence of stroke declined despite an increasing patient risk profile, and more than half of strokes occurred postoperatively rather than intraoperatively.

JAMA: 26 Jan 2011; 305:381-390
Tarakji KG, Sabik JF, Bhudia SK, Batizy LH, Blackstone EH
JAMA: 26 Jan 2011; 305:381-390 | PMID: 21266685
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Abstract

Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay.

Thomas EJ, Lucke JF, Wueste L, Weavind L, Patel B
Context: Telemedicine technology, which can enable intensivists to simultaneously monitor several intensive care units (ICUs) from an off-site location, is increasingly common, but there is little evidence to support its use. Objective: To assess the association of remote monitoring of ICU patients (ICU telemedicine [tele-ICU]) with mortality, complications, and length of stay (LOS). Design, setting, and patients: Observational study conducted in 6 ICUs of 5 hospitals in a large US health care system to assess the use of tele-ICU. The study included 2034 patients in the preintervention period (January 2003 to August 2005) and 2108 patients in the postintervention period (July 2004 to July 2006). Main outcome measures: Hospital and ICU mortality, complications, and hospital and ICU survivors\' LOS, with outcomes adjusted for severity of illness. Results: Local physicians delegated full treatment authority to the tele-ICU for 655 patients (31.1%) and authority to intervene only in life-threatening events for the remainder. Observed hospital mortality rates were 12.0% (95% confidence interval [CI], 10.6% to 13.5%) in the preintervention period and 9.9% (95% CI, 8.6% to 11.2%) in the postintervention period (preintervention to postintervention decrease, 2.1%; 95% CI, 0.2% to 4.1%; P = .03); observed ICU mortality rates were 9.2% (95% CI, 8.0% to 10.5%) in the preintervention period and 7.8% (95% CI, 6.7% to 9.0%) in the postintervention period (preintervention to postintervention decrease, 1.4%; 95% CI, -0.3% to 3.2%; P = .12). After adjustment for severity of illness, there were no significant differences associated with the telemedicine intervention for hospital mortality (relative risk, 0.85; 95% CI, 0.71 to 1.03) or for ICU mortality (relative risk, 0.88; 95% CI, 0.71 to 1.08). There was a significant interaction between the tele-ICU intervention and severity of illness (P < .001), in which tele-ICU was associated with improved survival in sicker patients but with no improvement or worse outcomes in less sick patients. There were no significant differences between the preintervention and postintervention periods for hospital or ICU LOS. Conclusion: Remote monitoring of ICU patients was not associated with an overall improvement in mortality or LOS.

JAMA: 30 Dec 2009; 302:2671-8
Thomas EJ, Lucke JF, Wueste L, Weavind L, Patel B
JAMA: 30 Dec 2009; 302:2671-8 | PMID: 20040555
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Abstract

Weight Change and Health Outcomes at 3 Years After Bariatric Surgery Among Individuals With Severe Obesity.

Courcoulas AP, Christian NJ, Belle SH, Berk PD, ... Wolfe BM, for the Longitudinal Assessment of Bariatric Surgery (LABS) Consortium
IMPORTANCE Severe obesity (body mass index [BMI] ≥35) is associated with a broad range of health risks. Bariatric surgery induces weight loss and short-term health improvements, but little is known about long-term outcomes of these operations. Objective To report 3-year change in weight and select health parameters after common bariatric surgical procedures. DESIGN AND SETTING The Longitudinal Assessment of Bariatric Surgery (LABS) Consortium is a multicenter observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. PARTICIPANTS AND EXPOSURE Adults undergoing first-time bariatric surgical procedures as part of routine clinical care by participating surgeons were recruited between 2006 and 2009 and followed up until September 2012. Participants completed research assessments prior to surgery and 6 months, 12 months, and then annually after surgery. MAIN OUTCOMES AND MEASURES Three years after Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB), we assessed percent weight change from baseline and the percentage of participants with diabetes achieving hemoglobin A1c levels less than 6.5% or fasting plasma glucose values less than 126 mg/dL without pharmacologic therapy. Dyslipidemia and hypertension resolution at 3 years was also assessed. RESULTS At baseline, participants (N = 2458) were 18 to 78 years old, 79% were women, median BMI was 45.9 (IQR, 41.7-51.5), and median weight was 129 kg (IQR, 115-147). For their first bariatric surgical procedure, 1738 participants underwent RYGB, 610 LAGB, and 110 other procedures. At baseline, 774 (33%) had diabetes, 1252 (63%) dyslipidemia, and 1601 (68%) hypertension. Three years after surgery, median actual weight loss for RYGB participants was 41 kg (IQR, 31-52), corresponding to a percentage of baseline weight lost of 31.5% (IQR, 24.6%-38.4%). For LAGB participants, actual weight loss was 20 kg (IQR, 10-29), corresponding to 15.9% (IQR, 7.9%-23.0%). The majority of weight loss was evident 1 year after surgery for both procedures. Five distinct weight change trajectory groups were identified for each procedure. Among participants who had diabetes at baseline, 216 RYGB participants (67.5%) and 28 LAGB participants (28.6%) experienced partial remission at 3 years. The incidence of diabetes was 0.9% after RYGB and 3.2% after LAGB. Dyslipidemia resolved in 237 RYGB participants (61.9%) and 39 LAGB participants (27.1%); remission of hypertension occurred in 269 RYGB participants (38.2%) and 43 LAGB participants (17.4%). CONCLUSIONS AND RELEVANCE Among participants with severe obesity, there was substantial weight loss 3 years after bariatric surgery, with the majority experiencing maximum weight change during the first year. However, there was variability in the amount and trajectories of weight loss and in diabetes, blood pressure, and lipid outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00465829.

JAMA: 04 Nov 2013; epub ahead of print
Courcoulas AP, Christian NJ, Belle SH, Berk PD, ... Wolfe BM, for the Longitudinal Assessment of Bariatric Surgery (LABS) Consortium
JAMA: 04 Nov 2013; epub ahead of print | PMID: 24189773
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Abstract

Mechanical Chest Compressions and Simultaneous Defibrillation vs Conventional Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest: The LINC Randomized Trial.

Rubertsson S, Lindgren E, Smekal D, Ostlund O, ... Herlitz J, Karlsten R
IMPORTANCE A strategy using mechanical chest compressions might improve the poor outcome in out-of-hospital cardiac arrest, but such a strategy has not been tested in large clinical trials. Objective To determine whether administering mechanical chest compressions with defibrillation during ongoing compressions (mechanical CPR), compared with manual cardiopulmonary resuscitation (manual CPR), according to guidelines, would improve 4-hour survival. Design, setting, and participants Multicenter randomized clinical trial of 2589 patients with out-of-hospital cardiac arrest conducted between January 2008 and February 2013 in 4 Swedish, 1 British, and 1 Dutch ambulance services and their referring hospitals. Duration of follow-up was 6 months. INTERVENTIONS Patients were randomized to receive either mechanical chest compressions (LUCAS Chest Compression System, Physio-Control/Jolife AB) combined with defibrillation during ongoing compressions (n = 1300) or to manual CPR according to guidelines (n = 1289). MAIN OUTCOMES AND MEASURES Four-hour survival, with secondary end points of survival up to 6 months with good neurological outcome using the Cerebral Performance Category (CPC) score. A CPC score of 1 or 2 was classified as a good outcome. RESULTS Four-hour survival was achieved in 307 patients (23.6%) with mechanical CPR and 305 (23.7%) with manual CPR (risk difference, -0.05%; 95% CI, -3.3% to 3.2%; P &gt; .99). Survival with a CPC score of 1 or 2 occurred in 98 (7.5%) vs 82 (6.4%) (risk difference, 1.18%; 95% CI, -0.78% to 3.1%) at intensive care unit discharge, in 108 (8.3%) vs 100 (7.8%) (risk difference, 0.55%; 95% CI, -1.5% to 2.6%) at hospital discharge, in 105 (8.1%) vs 94 (7.3%) (risk difference, 0.78%; 95% CI, -1.3% to 2.8%) at 1 month, and in 110 (8.5%) vs 98 (7.6%) (risk difference, 0.86%; 95% CI, -1.2% to 3.0%) at 6 months with mechanical CPR and manual CPR, respectively. Among patients surviving at 6 months, 99% in the mechanical CPR group and 94% in the manual CPR group had CPC scores of 1 or 2. CONCLUSIONS AND RELEVANCE Among adults with out-of-hospital cardiac arrest, there was no significant difference in 4-hour survival between patients treated with the mechanical CPR algorithm or those treated with guideline-adherent manual CPR. The vast majority of survivors in both groups had good neurological outcomes by 6 months. In clinical practice, mechanical CPR using the presented algorithm did not result in improved effectiveness compared with manual CPR. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00609778.

JAMA: 17 Nov 2013; epub ahead of print
Rubertsson S, Lindgren E, Smekal D, Ostlund O, ... Herlitz J, Karlsten R
JAMA: 17 Nov 2013; epub ahead of print | PMID: 24240611
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Abstract

Quality of Care and Patient Outcomes in Critical Access Rural Hospitals.

Joynt KE, Harris Y, Orav EJ, Jha AK
Context Critical access hospitals (CAHs) play a crucial role in the US rural safety net. Current policy efforts have focused primarily on helping these small, isolated hospitals remain financially viable to ensure access for individuals living in rural areas in the United States; however, little is known about the quality of care they provide or the outcomes their patients achieve. Objectives To examine the quality of care and patient outcomes at CAHs and to understand why patterns of care might differ for CAHs vs non-CAHs. Design, Setting, and Patients A retrospective analysis in 4738 US hospitals of Medicare fee-for-service beneficiaries with acute myocardial infarction (AMI) (10 703 for CAHs vs 469 695 for non-CAHs), congestive heart failure (CHF) (52 927 for CAHs vs 958 790 for non-CAHs), and pneumonia (86 359 for CAHs vs 773 227 for non-CAHs) who were discharged in 2008-2009. Main Outcome Measures Clinical capabilities, performance on processes of care, and 30-day mortality rates, adjusted for age, sex, race, and medical comorbidities. Results Compared with other hospitals (n = 3470), 1268 CAHs (26.8%) were less likely to have intensive care units (380 [30.0%] vs 2581 [74.4%], P < .001), cardiac catheterization capabilities (6 [0.5%] vs 1654 [47.7%], P < .001), and at least basic electronic health records (80 [6.5%] vs 445 [13.9%], P < .001). The CAHs had lower performance on processes of care than non-CAHs for all 3 conditions examined (concordance with Hospital Quality Alliance process measures for AMI, 91.0% [95% CI, 89.7%-92.3%] vs 97.8% [95% CI, 97.7%-97.9%]; for CHF, 80.6% [95% CI, 79.2%-82.0%] vs 93.5% [95% CI, 93.3%-93.7%]; and for pneumonia, 89.3% [95% CI, 88.6%-90.0%] vs 93.7% [95% CI, 93.6%-93.9%]; P < .001 for each). Patients admitted to CAHs had higher 30-day mortality rates for each condition than those admitted to non-CAHs (for AMI: 23.5% vs 16.2%; adjusted odds ratio [OR], 1.70; 95% confidence interval [CI], 1.61-1.80; P < .001; for CHF: 13.4% vs 10.9%; adjusted OR, 1.28; 95% CI, 1.23-1.32; P < .001; and for pneumonia: 14.1% vs 12.1%; adjusted OR, 1.20; 95% CI, 1.16-1.24; P < .001). Conclusion Compared with non-CAHs, CAHs had fewer clinical capabilities, worse measured processes of care, and higher mortality rates for patients with AMI, CHF, or pneumonia.

JAMA: 06 Jul 2011; 306:45-52
Joynt KE, Harris Y, Orav EJ, Jha AK
JAMA: 06 Jul 2011; 306:45-52 | PMID: 21730240
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Abstract

Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial.

Snitz BE, O\'Meara ES, Carlson MC, Arnold AM, ... DeKosky ST,
Context: The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning. Objective: To determine whether G. biloba slows the rates of global or domain-specific cognitive decline in older adults. Design, setting, and participants: The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years. Intervention: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or identical-appearing placebo (n = 1524). Main outcome measures: Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests. Results: Annual rates of decline in z scores did not differ between G. biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05). Conclusion: Compared with placebo, the use of G. biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment. Trial registration: clinicaltrials.gov Identifier: NCT00010803.

JAMA: 30 Dec 2009; 302:2663-70
Snitz BE, O'Meara ES, Carlson MC, Arnold AM, ... DeKosky ST,
JAMA: 30 Dec 2009; 302:2663-70 | PMID: 20040554
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Abstract

Soy food intake and breast cancer survival.

Shu XO, Zheng Y, Cai H, Gu K, ... Zheng W, Lu W
Context: Soy foods are rich in isoflavones, a major group of phytoestrogens that have been hypothesized to reduce the risk of breast cancer. However, the estrogen-like effect of isoflavones and the potential interaction between isoflavones and tamoxifen have led to concern about soy food consumption among breast cancer patients. Objective: To evaluate the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence. Design, setting, and participants: The Shanghai Breast Cancer Survival Study, a large, population-based cohort study of 5042 female breast cancer survivors in China. Women aged 20 to 75 years with diagnoses between March 2002 and April 2006 were recruited and followed up through June 2009. Information on cancer diagnosis and treatment, lifestyle exposures after cancer diagnosis, and disease progression was collected at approximately 6 months after cancer diagnosis and was reassessed at 3 follow-up interviews conducted at 18, 36, and 60 months after diagnosis. Annual record linkage with the Shanghai Vital Statistics Registry database was carried out to obtain survival information for participants who were lost to follow-up. Medical charts were reviewed to verify disease and treatment information. Main outcome measures: Total mortality and breast cancer recurrence or breast cancer-related deaths. Cox regression analysis was carried out with adjustment for known clinical predictors and other lifestyle factors. Soy food intake was treated as a time-dependent variable. Results: During the median follow-up of 3.9 years (range, 0.5-6.2 years), 444 deaths and 534 recurrences or breast cancer-related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54-0.92) for total mortality and 0.68 (95% CI, 0.54-0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4-year mortality rates were 10.3% and 7.4%, and the 4-year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor-positive or -negative breast cancer and was present in both users and nonusers of tamoxifen. Conclusion: Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.

JAMA: 09 Dec 2009; 302:2437-43
Shu XO, Zheng Y, Cai H, Gu K, ... Zheng W, Lu W
JAMA: 09 Dec 2009; 302:2437-43 | PMID: 19996398
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Abstract

Effects of Immediate Blood Pressure Reduction on Death and Major Disability in Patients With Acute Ischemic Stroke: The CATIS Randomized Clinical Trial.

He J, Zhang Y, Xu T, Zhao Q, ... Chen J, for the CATIS Investigators
IMPORTANCE Although the benefit of reducing blood pressure for primary and secondary prevention of stroke has been established, the effect of antihypertensive treatment in patients with acute ischemic stroke is uncertain. Objective To evaluate whether immediate blood pressure reduction in patients with acute ischemic stroke would reduce death and major disability at 14 days or hospital discharge. Design, setting, and participants The China Antihypertensive Trial in Acute Ischemic Stroke, a single-blind, blinded end-points randomized clinical trial, conducted among 4071 patients with nonthrombolysed ischemic stroke within 48 hours of onset and elevated systolic blood pressure. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. INTERVENTIONS Patients (n = 2038) were randomly assigned to receive antihypertensive treatment (aimed at lowering systolic blood pressure by 10% to 25% within the first 24 hours after randomization, achieving blood pressure less than 140/90 mm Hg within 7 days, and maintaining this level during hospitalization) or to discontinue all antihypertensive medications (control) during hospitalization (n = 2033). MAIN OUTCOMES AND MEASURES Primary outcome was a combination of death and major disability (modified Rankin Scale score ≥3) at 14 days or hospital discharge. RESULTS Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg (-12.7%) within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg (-7.2%) in the control group within 24 hours after randomization (difference, -5.5% [95% CI, -4.9 to -6.1%]; absolute difference, -9.1 mm Hg [95% CI, -10.2 to -8.1]; P &lt; .001). Mean systolic blood pressure was 137.3 mm Hg in the antihypertensive treatment group and 146.5 mm Hg in the control group at day 7 after randomization (difference, -9.3 mm Hg [95% CI, -10.1 to -8.4]; P &lt; .001). The primary outcome did not differ between treatment groups (683 events [antihypertensive treatment] vs 681 events [control]; odds ratio, 1.00 [95% CI, 0.88 to 1.14]; P = .98) at 14 days or hospital discharge. The secondary composite outcome of death and major disability at 3-month posttreatment follow-up did not differ between treatment groups (500 events [antihypertensive treatment] vs 502 events [control]; odds ratio, 0.99 [95% CI, 0.86 to 1.15]; P = .93). CONCLUSION AND RELEVANCE Among patients with acute ischemic stroke, blood pressure reduction with antihypertensive medications, compared with the absence of hypertensive medication, did not reduce the likelihood of death and major disability at 14 days or hospital discharge. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01840072.

JAMA: 17 Nov 2013; epub ahead of print
He J, Zhang Y, Xu T, Zhao Q, ... Chen J, for the CATIS Investigators
JAMA: 17 Nov 2013; epub ahead of print | PMID: 24240777
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Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial.

Morelli A, Ertmer C, Westphal M, Rehberg S, ... Mebazaa A, Singer M
IMPORTANCE β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. Objective To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock. Design, setting, and patients Open-label, randomized phase 2 study, conducted in a university hospital intensive care unit (ICU) between November 2010 and July 2012, involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher. INTERVENTIONS We randomly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to standard treatment. MAIN OUTCOMES AND MEASURES Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Secondary outcomes included hemodynamic and organ function measures; norepinephrine dosages at 24, 48, 72, and 96 hours; and adverse events and mortality occurring within 28 days after randomization. RESULTS Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was -28/min (IQR, -37 to -21) for the esmolol group vs -6/min (95% CI, -14 to 0) for the control group with a mean reduction of 18/min (P &lt; .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, -1 to 10) vs 1 mL/m2 for the control group (IQR, -3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, -2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was -0.1 mmol/L (IQR, -0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, -0.3 for 0.6; P = .007); for norepinephrine, -0.11 μg/kg/min (IQR, -0.46 to 0.02) for the esmolol group vs -0.01 μg/kg/min (IQR, -0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P &lt; .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P &lt; .001). CONCLUSIONS AND RELEVANCE For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01231698.

JAMA: 09 Oct 2013; epub ahead of print
Morelli A, Ertmer C, Westphal M, Rehberg S, ... Mebazaa A, Singer M
JAMA: 09 Oct 2013; epub ahead of print | PMID: 24108526
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Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion.

Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, ... Staessen JA, for the European Project on Genes in Hypertension (EPOGH) Investigators
Context Extrapolations from observational studies and short-term intervention trials suggest that population-wide moderation of salt intake might reduce cardiovascular events. Objective To assess whether 24-hour urinary sodium excretion predicts blood pressure (BP) and health outcomes. Design, Setting, and Participants Prospective population study, involving 3681 participants without cardiovascular disease (CVD) who are members of families that were randomly enrolled in the Flemish Study on Genes, Environment, and Health Outcomes (1985-2004) or in the European Project on Genes in Hypertension (1999-2001). Of 3681 participants without CVD, 2096 were normotensive at baseline and 1499 had BP and sodium excretion measured at baseline and last follow-up (2005-2008). Main Outcome Measures Incidence of mortality and morbidity and association between changes in BP and sodium excretion. Multivariable-adjusted hazard ratios (HRs) express the risk in tertiles of sodium excretion relative to average risk in the whole study population. Results Among 3681 participants followed up for a median 7.9 years, CVD deaths decreased across increasing tertiles of 24-hour sodium excretion, from 50 deaths in the low (mean, 107 mmol), 24 in the medium (mean, 168 mmol), and 10 in the high excretion group (mean, 260 mmol; P < .001), resulting in respective death rates of 4.1% (95% confidence interval [CI], 3.5%-4.7%), 1.9% (95% CI, 1.5%-2.3%), and 0.8% (95% CI, 0.5%-1.1%). In multivariable-adjusted analyses, this inverse association retained significance (P = .02): the HR in the low tertile was 1.56 (95% CI, 1.02-2.36; P = .04). Baseline sodium excretion predicted neither total mortality (P = .10) nor fatal combined with nonfatal CVD events (P = .55). Among 2096 participants followed up for 6.5 years, the risk of hypertension did not increase across increasing tertiles (P = .93). Incident hypertension was 187 (27.0%; HR, 1.00; 95% CI, 0.87-1.16) in the low, 190 (26.6%; HR, 1.02; 95% CI, 0.89-1.16) in the medium, and 175 (25.4%; HR, 0.98; 95% CI, 0.86-1.12) in the high sodium excretion group. In 1499 participants followed up for 6.1 years, systolic blood pressure increased by 0.37 mm Hg per year (P < .001), whereas sodium excretion did not change (-0.45 mmol per year, P = .15). However, in multivariable-adjusted analyses, a 100-mmol increase in sodium excretion was associated with 1.71 mm Hg increase in systolic blood pressure (P.<001) but no change in diastolic BP. Conclusions In this population-based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications. Lower sodium excretion was associated with higher CVD mortality.

JAMA: 04 May 2011; 305:1777-1785
Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, ... Staessen JA, for the European Project on Genes in Hypertension (EPOGH) Investigators
JAMA: 04 May 2011; 305:1777-1785 | PMID: 21540421
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Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

Benjamin DK, Hudak ML, Duara S, Randolph DA, ... Smith PB, Fluconazole Prophylaxis Study Team
IMPORTANCE Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. Objective To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. Design, setting, and patients This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00734539.

JAMA: 04 May 2014; 311:1742-9
Benjamin DK, Hudak ML, Duara S, Randolph DA, ... Smith PB, Fluconazole Prophylaxis Study Team
JAMA: 04 May 2014; 311:1742-9 | PMID: 24794367
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2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8).

James PA, Oparil S, Carter BL, Cushman WC, ... Narva AS, Ortiz E
Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.

JAMA: 18 Dec 2013; epub ahead of print
James PA, Oparil S, Carter BL, Cushman WC, ... Narva AS, Ortiz E
JAMA: 18 Dec 2013; epub ahead of print | PMID: 24352797
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Abstract

Trends in Length of Stay and Short-term Outcomes Among Medicare Patients Hospitalized for Heart Failure, 1993-2006.

Bueno H, Ross JS, Wang Y, Chen J, ... Kosiborod M, Krumholz HM
Context: Whether decreases in the length of stay during the past decade for patients with heart failure (HF) may be associated with changes in outcomes is unknown. Objective: To describe the temporal changes in length of stay, discharge disposition, and short-term outcomes among older patients hospitalized for HF. Design, setting, and participants: An observational study of 6 955 461 Medicare fee-for-service hospitalizations for HF between 1993 and 2006, with a 30-day follow-up. Main outcome measures: Length of hospital stay, in-patient and 30-day mortality, and 30-day readmission rates. Results: Between 1993 and 2006, mean length of stay decreased from 8.81 days (95% confidence interval [CI], 8.79-8.83 days) to 6.33 days (95% CI, 6.32-6.34 days). In-hospital mortality decreased from 8.5% (95% CI, 8.4%-8.6%) in 1993 to 4.3% (95% CI, 4.2%-4.4%) in 2006, whereas 30-day mortality decreased from 12.8% (95% CI, 12.8%-12.9%) to 10.7% (95% CI, 10.7%-10.8%). Discharges to home or under home care service decreased from 74.0% to 66.9% and discharges to skilled nursing facilities increased from 13.0% to 19.9%. Thirty-day readmission rates increased from 17.2% (95% CI, 17.1%-17.3%) to 20.1% (95% CI, 20.0%-20.2%; all P < .001). Consistent with the unadjusted analyses, the 2005-2006 risk-adjusted 30-day mortality risk ratio was 0.92 (95% CI, 0.91-0.93) compared with 1993-1994, and the 30-day readmission risk ratio was 1.11 (95% CI, 1.10-1.11). Conclusion: For patients admitted with HF during the past 14 years, reductions in length of stay and in-hospital mortality, less marked reductions in 30-day mortality, and changes in discharge disposition accompanied by increases in 30-day readmission rates were observed.

JAMA: 02 Jun 2010; 303:2141-7
Bueno H, Ross JS, Wang Y, Chen J, ... Kosiborod M, Krumholz HM
JAMA: 02 Jun 2010; 303:2141-7 | PMID: 20516414
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Abstract

Effect of Statin Therapy on Mortality in Patients With Ventilator-Associated Pneumonia: A Randomized Clinical Trial.

Papazian L, Roch A, Charles PE, Penot-Ragon C, ... Forel JM, for the STATIN-VAP Study Group
IMPORTANCE Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality. Objective To determine whether statin therapy can decrease day-28 mortality in patients with VAP. Design, setting, and participants Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients. INTERVENTIONS Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first. MAIN OUTCOMES AND MEASURES Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14. RESULTS The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, -3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, -1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score. CONCLUSIONS AND RELEVANCE In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01057758.

JAMA: 09 Oct 2013; epub ahead of print
Papazian L, Roch A, Charles PE, Penot-Ragon C, ... Forel JM, for the STATIN-VAP Study Group
JAMA: 09 Oct 2013; epub ahead of print | PMID: 24108510
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Abstract

Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes.

Roumie CL, Greevy RA, Grijalva CG, Hung AM, ... Elasy TA, Griffin MR
IMPORTANCE Preferred second-line medication for diabetes treatment after metformin failure remains uncertain. Objective To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea. Design, setting, and participants Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses. MAIN OUTCOMES AND MEASURES Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities. RESULTS Among 178 341 metformin monotherapy patients, 2948 added insulin and 39 990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12 180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87). CONCLUSIONS AND RELEVANCE Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.

JAMA: 10 Jun 2014; 311:2288-96
Roumie CL, Greevy RA, Grijalva CG, Hung AM, ... Elasy TA, Griffin MR
JAMA: 10 Jun 2014; 311:2288-96 | PMID: 24915260
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Abstract

How to use a subgroup analysis: users\' guide to the medical literature.

Sun X, Ioannidis JP, Agoritsas T, Alba AC, Guyatt G
Clinicians, when trying to apply trial results to patient care, need to individualize patient care and, potentially, manage patients based on results of subgroup analyses. Apparently compelling subgroup effects often prove spurious, and guidance is needed to differentiate credible from less credible subgroup claims. We therefore provide 5 criteria to use when assessing the validity of subgroup analyses: (1) Can chance explain the apparent subgroup effect; (2) Is the effect consistent across studies; (3) Was the subgroup hypothesis one of a small number of hypotheses developed a priori with direction specified; (4) Is there strong preexisting biological support; and (5) Is the evidence supporting the effect based on within- or between-study comparisons. The first 4 criteria are applicable to individual studies or systematic reviews, the last only to systematic reviews of multiple studies. These criteria will help clinicians deciding whether to use subgroup analyses to guide their patient care.

JAMA: 21 Jan 2014; 311:405-11
Sun X, Ioannidis JP, Agoritsas T, Alba AC, Guyatt G
JAMA: 21 Jan 2014; 311:405-11 | PMID: 24449319
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Abstract

Tremor.

Elias WJ, Shah BB
Tremor, defined as a rhythmic and involuntary movement of any body part, is the most prevalent movement disorder, affecting millions of people in the United States. All adults have varying degrees of physiological tremor so it is imperative to distinguish physiological tremor from pathological tremor types. Tremor is not inherently dangerous, but it can cause significant disability at home and in the workplace. Common tremors like essential tremor and Parkinson disease tremor can be recognized by most clinicians at the early stages for the initiation of disease-specific medical therapies. Less common tremors, such as those induced by drugs or brain lesions, are also important to recognize because they may be more refractory to medical therapies and may require earlier referral to a neurological specialist. In patients with the most progressive and severe tremors that are resistant to medical therapies, surgical interventions are available and typically target deep brain regions with stimulation or lesioning. This Grand Rounds review describes the evaluation and evidence-based management of the most common tremors, essential tremor and Parkinson disease tremor.

JAMA: 04 Mar 2014; 311:948-54
Elias WJ, Shah BB
JAMA: 04 Mar 2014; 311:948-54 | PMID: 24595779
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Abstract

Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009.

Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, ... Hamman RF, SEARCH for Diabetes in Youth Study
IMPORTANCE Despite concern about an "epidemic," there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups. Objective To estimate changes in the prevalence of type 1 and type 2 diabetes in US youth, by sex, age, and race/ethnicity between 2001 and 2009. Design, setting, and participants Case patients were ascertained in 4 geographic areas and 1 managed health care plan. The study population was determined by the 2001 and 2009 bridged-race intercensal population estimates for geographic sites and membership counts for the health plan. MAIN OUTCOMES AND MEASURES Prevalence (per 1000) of physician-diagnosed type 1 diabetes in youth aged 0 through 19 years and type 2 diabetes in youth aged 10 through 19 years. RESULTS In 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52). In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88-1.97). In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62) and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47) and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians). Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%) increase in type 1 diabetes over 8 years. In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37). In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49). In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51); 1.06 per 1000 among black youth (95% CI, 0.93-1.22); 0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88); and 0.17 per 1000 among white youth (95% CI, 0.15-0.20). Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians. Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%) overall increase in type 2 diabetes. CONCLUSIONS AND RELEVANCE Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased. Further studies are required to determine the causes of these increases.

JAMA: 04 May 2014; 311:1778-86
Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, ... Hamman RF, SEARCH for Diabetes in Youth Study
JAMA: 04 May 2014; 311:1778-86 | PMID: 24794371
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Abstract

Effect of Progenitor Cell Mobilization With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Peripheral Artery Disease: A Randomized Clinical Trial.

Poole J, Mavromatis K, Binongo JN, Khan A, ... Waller EK, Quyyumi AA
IMPORTANCE Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. Objective To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. Design, setting, and participants In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01041417.

JAMA: 18 Nov 2013; epub ahead of print
Poole J, Mavromatis K, Binongo JN, Khan A, ... Waller EK, Quyyumi AA
JAMA: 18 Nov 2013; epub ahead of print | PMID: 24247554
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Abstract

Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging.

Lieb W, Beiser AS, Vasan RS, Tan ZS, ... Wolf PA, Seshadri S
Context: The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). Objective: To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. Design, setting, and participants: Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. Main outcome measure: Incidence of dementia and AD during follow-up until December 31, 2007. Results: During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. Conclusion: Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults.

JAMA: 16 Dec 2009; 302:2565-72
Lieb W, Beiser AS, Vasan RS, Tan ZS, ... Wolf PA, Seshadri S
JAMA: 16 Dec 2009; 302:2565-72 | PMID: 20009056
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Abstract

The anatomy of health care in the United States.

Moses H, Matheson DH, Dorsey ER, George BP, Sadoff D, Yoshimura S
Health care in the United States includes a vast array of complex interrelationships among those who receive, provide, and finance care. In this article, publicly available data were used to identify trends in health care, principally from 1980 to 2011, in the source and use of funds ("economic anatomy"), the people receiving and organizations providing care, and the resulting value created and health outcomes. In 2011, US health care employed 15.7% of the workforce, with expenditures of $2.7 trillion, doubling since 1980 as a percentage of US gross domestic product (GDP) to 17.9%. Yearly growth has decreased since 1970, especially since 2002, but, at 3% per year, exceeds any other industry and GDP overall. Government funding increased from 31.1% in 1980 to 42.3% in 2011. Despite the increases in resources devoted to health care, multiple health metrics, including life expectancy at birth and survival with many diseases, shows the United States trailing peer nations. The findings from this analysis contradict several common assumptions. Since 2000, (1) price (especially of hospital charges [+4.2%/y], professional services [3.6%/y], drugs and devices [+4.0%/y], and administrative costs [+5.6%/y]), not demand for services or aging of the population, produced 91% of cost increases; (2) personal out-of-pocket spending on insurance premiums and co-payments have declined from 23% to 11%; and (3) chronic illnesses account for 84% of costs overall among the entire population, not only of the elderly. Three factors have produced the most change: (1) consolidation, with fewer general hospitals and more single-specialty hospitals and physician groups, producing financial concentration in health systems, insurers, pharmacies, and benefit managers; (2) information technology, in which investment has occurred but value is elusive; and (3) the patient as consumer, whereby influence is sought outside traditional channels, using social media, informal networks, new public sources of information, and self-management software. These forces create tension among patient aims for choice, personal care, and attention; physician aims for professionalism and autonomy; and public and private payer aims for aggregate economic value across large populations. Measurements of cost and outcome (applied to groups) are supplanting individuals\' preferences. Clinicians increasingly are expected to substitute social and economic goals for the needs of a single patient. These contradictory forces are difficult to reconcile, creating risk of growing instability and political tensions. A national conversation, guided by the best data and information, aimed at explicit understanding of choices, tradeoffs, and expectations, using broader definitions of health and value, is needed.

JAMA: 12 Nov 2013; 310:1947-63
Moses H, Matheson DH, Dorsey ER, George BP, Sadoff D, Yoshimura S
JAMA: 12 Nov 2013; 310:1947-63 | PMID: 24219951
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Abstract

Strength of study evidence examined by the FDA in premarket approval of cardiovascular devices.

Dhruva SS, Bero LA, Redberg RF
Context: Medical devices are common in clinical practice and have important effects on morbidity and mortality, yet there has not been a systematic examination of evidence used by the US Food and Drug Administration (FDA) for device approval. ObjectiveS: To study premarket approval (PMA)--the most stringent FDA review process--of cardiovascular devices and to characterize the type and strength of evidence on which it is based. Data Sources and Study selection: Systematic review of 123 summaries of safety and effectiveness data for 78 PMAs for high-risk cardiovascular devices that received PMA between January 2000 and December 2007. Data extraction: Examination of the methodological characteristics considered essential to minimize confounding and bias, as well as the primary end points of the 123 studies supporting the PMAs. Results: Thirty-three of 123 studies (27%) used to support recent FDA approval of cardiovascular devices were randomized and 17 of 123 (14%) were blinded. Fifty-one of 78 PMAs (65%) were based on a single study. One hundred eleven of 213 primary end points (52%) were compared with controls and 34 of 111 controls (31%) were retrospective. One hundred eighty-seven of 213 primary end points (88%) were surrogate measures and 122 of 157 (78%) had a discrepancy between the number of patients enrolled in the study and the number analyzed. Conclusion: Premarket approval of cardiovascular devices by the FDA is often based on studies that lack adequate strength and may be prone to bias.

JAMA: 30 Dec 2009; 302:2679-85
Dhruva SS, Bero LA, Redberg RF
JAMA: 30 Dec 2009; 302:2679-85 | PMID: 20040556
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Abstract

Fibromyalgia: a clinical review.

Clauw DJ
IMPORTANCE Fibromyalgia is present in as much as 2% to 8% of the population, is characterized by widespread pain, and is often accompanied by fatigue, memory problems, and sleep disturbances. Objective To review the epidemiology, pathophysiology, diagnosis, and treatment of fibromyalgia. EVIDENCE REVIEW The medical literature on fibromyalgia was reviewed from 1955 to March 2014 via MEDLINE and the Cochrane Central Registry of Controlled Trials, with an emphasis on meta-analyses and contemporary evidence-based treatment guidelines. Treatment recommendations are based on the most recent evidence-based guidelines from the Canadian Pain Society and graded from 1 to 5 based on the level of available evidence. FINDINGS Numerous treatments are available for managing fibromyalgia that are supported by high-quality evidence. These include nonpharmacological therapies (education, exercise, cognitive behavioral therapy) and pharmacological therapies (tricyclics, serotonin norepinephrine reuptake inhibitors, and gabapentinoids). CONCLUSIONS AND RELEVANCE Fibromyalgia and other "centralized" pain states are much better understood now than ever before. Fibromyalgia may be considered as a discrete diagnosis or as a constellation of symptoms characterized by central nervous system pain amplification with concomitant fatigue, memory problems, and sleep and mood disturbances. Effective treatment for fibromyalgia is now possible.

JAMA: 15 Apr 2014; 311:1547-55
Clauw DJ
JAMA: 15 Apr 2014; 311:1547-55 | PMID: 24737367
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Abstract

Plasma clusterin and the risk of Alzheimer disease.

Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM
Context Variants in the clusterin gene are associated with the risk of Alzheimer disease (AD) and clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in patients with AD. Objective To evaluate the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. Design, Setting, and Participants A case-cohort study nested within the Rotterdam Study, a prospective population-based cohort study conducted in Rotterdam, the Netherlands. Plasma levels of clusterin were measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Main Outcome Measures Prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. Results The likelihood of prevalent AD increased with increasing plasma levels of clusterin (odds ratio [OR] per SD increase of plasma clusterin level, 1.63; 95% confidence interval [CI], 1.21-2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, -1.36; 95% CI, -2.70 to -0.02; P = .047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted HR, 1.00; 95% CI, 0.85-1.17; P for trend = .77) or within 3 years of baseline (adjusted HR, 1.09; 95% CI, 0.84-1.42; P for trend = .65). Conclusion Plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD.

JAMA: 06 Apr 2011; 305:1322-6
Schrijvers EM, Koudstaal PJ, Hofman A, Breteler MM
JAMA: 06 Apr 2011; 305:1322-6 | PMID: 21467285
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Abstract

Management of asymptomatic internal carotid artery stenosis.

Beckman JA
Optimal management of patients with asymptomatic carotid artery stenosis remains unclear. Although 2 high-quality randomized clinical trials demonstrated reductions in ispsilateral stroke rates in patients without symptoms after carotid endarterectomy, medical therapy of asymptomatic carotid artery stenosis has reduced rates of stroke to approximately 1% per year, raising questions about the generalizability of these previous trials to current medical practice. However, reductions in adverse events after revascularization can make revascularization more attractive. The emergence of percutaneous revascularization for carotid artery stenosis has raised further questions about optimal management of asymptomatic carotid artery stenosis. This Grand Rounds summarizes the factors to consider when counseling patients and making clinical decisions regarding medical therapy and revascularization for patients with asymptomatic carotid artery stenosis. This information should provide clinicians with the knowledge base to counsel patients about the risks and benefits of treatment options.

JAMA: 15 Oct 2013; 310:1612-8
Beckman JA
JAMA: 15 Oct 2013; 310:1612-8 | PMID: 24129465
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Abstract

Decline in Estimated Glomerular Filtration Rate and Subsequent Risk of End-Stage Renal Disease and Mortality.

Coresh J, Turin TC, Matsushita K, Sang Y, ... Levey AS, for the CKD Prognosis Consortium
IMPORTANCE The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of -57% or greater) is a late event. Objective To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated. Data sources AND STUDY SELECTION Individual meta-analysis of 1.7 million participants with 12 344 ESRD events and 223 944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data. DATA EXTRACTION AND SYNTHESIS Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012. MAIN OUTCOMES AND MEASURES End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR. RESULTS The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of -57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of -30%. However, changes of -30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of -57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of -57%, was 83% (95% CI, 71%-93%) for estimated GFR change of -40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of -30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern. CONCLUSIONS AND RELEVANCE Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

JAMA: 02 Jun 2014; epub ahead of print
Coresh J, Turin TC, Matsushita K, Sang Y, ... Levey AS, for the CKD Prognosis Consortium
JAMA: 02 Jun 2014; epub ahead of print | PMID: 24892770
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Abstract

Acute Skeletal Muscle Wasting in Critical Illness.

Puthucheary ZA, Rawal J, McPhail M, Connolly B, ... Hart N, Montgomery HE
IMPORTANCE Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. Objective To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. Design, setting, and participants Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. MAIN OUTCOMES AND MEASURES Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. RESULTS There were significant reductions in the rectus femoris CSA observed at day 10 (-17.7% [95% CI, -25.9% to 8.1%]; P &lt; .001). In the 28 patients assessed by all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1% to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (-15.7%; 95% CI, -27.7% to 11.4%) compared with single organ failure (-3.0%; 95% CI, -5.3% to 2.1%) (P &lt; .001), even by day 3 (-8.7% [95% CI, -59.3% to 50.6%] vs -1.8% [95% CI, -12.3% to 10.5%], respectively; P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) (P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = -0.83, P = .005) and decreased synthesis (n = 9, r = -0.69, P = .04). CONCLUSIONS AND RELEVANCE Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.

JAMA: 09 Oct 2013; epub ahead of print
Puthucheary ZA, Rawal J, McPhail M, Connolly B, ... Hart N, Montgomery HE
JAMA: 09 Oct 2013; epub ahead of print | PMID: 24108501
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Abstract

Proportion of US Adults Potentially Affected by the 2014 Hypertension Guideline.

Navar-Boggan AM, Pencina MJ, Williams K, Sniderman AD, Peterson ED
IMPORTANCE The new 2014 blood pressure (BP) guideline released by the panel members appointed to the Eighth Joint National Committee (JNC 8; 2014 BP guideline) proposed less restrictive BP targets for adults aged 60 years or older and for those with diabetes and chronic kidney disease. Objective To estimate the proportion of US adults potentially affected by recent changes in recommendations for management of hypertension. DESIGN Cross-sectional, nationally representative survey. PARTICIPANTS Using data from the National Health and Nutrition Examination Survey between 2005 and 2010 (n = 16 372), we evaluated hypertension control and treatment recommendations for US adults. MAIN OUTCOMES AND MEASURES Proportion of adults estimated to meet guideline-based BP targets under the 2014 BP guideline and under the previous seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guideline. RESULTS The proportion of younger adults (18-59 years) with treatment-eligible hypertension under the JNC 7 guideline was 20.3% (95% CI, 19.1%-21.4%) and decreased to 19.2% (95% CI, 18.1%-20.4%) under the 2014 BP guideline. Larger declines were observed among older adults (≥60 years), decreasing from 68.9% (95% CI, 66.9%-70.8%) under JNC 7 to 61.2% (95% CI, 59.3%-63.0%) under the 2014 BP guideline. The proportion of adults with treatment-eligible hypertension who met BP goals increased slightly for younger adults, from 41.2% (95% CI, 38.1%-44.3%) under JNC 7 to 47.5% (95% CI, 44.4%-50.6%) under the 2014 BP guideline, and more substantially for older adults, from 40.0% (95% CI, 37.8%-42.3%) under JNC 7 to 65.8% (95% CI, 63.7%-67.9%) under the 2014 BP guideline. Overall, 1.6% (95% CI, 1.3%-1.9%) of US adults aged 18-59 years and 27.6% (95% CI, 25.9%-29.3%) of adults aged 60 years or older were receiving BP-lowering medication and meeting more stringent JNC 7 targets. These patients may be eligible for less stringent or no BP therapy with the 2014 BP guideline. CONCLUSIONS AND RELEVANCE Compared with the JNC 7 guideline, the 2014 BP guideline from the panel members appointed to the JNC 8 was associated with a reduction in the proportion of US adults recommended for hypertension treatment and a substantial increase in the proportion of adults considered to have achieved goal BP, primarily in older adults.

JAMA: 30 Mar 2014; epub ahead of print
Navar-Boggan AM, Pencina MJ, Williams K, Sniderman AD, Peterson ED
JAMA: 30 Mar 2014; epub ahead of print | PMID: 24682242
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Abstract

Hospitals, market share, and consolidation.

Cutler DM, Scott Morton F
A large reduction in use of inpatient care combined with the incentives in the Affordable Care Act is leading to significant consolidation in the hospital industry. What was once a set of independent hospitals having arms-length relationships with physicians and clinicians who provide ambulatory care is becoming a small number of locally integrated health systems, generally built around large, prestigious academic medical centers. The typical region in the United States has 3 to 5 consolidated health systems, spanning a wide range of care settings, and a smaller fringe of health care centers outside those systems. Consolidated health systems have advantages and drawbacks. The advantages include the ability to coordinate care across different practitioners and sites of care. Offsetting this is the potential for higher prices resulting from greater market power. Market power increases because it is difficult for insurers to bargain successfully with one of only a few health systems. Antitrust authorities are examining these consolidated systems as they form, but broad conclusions are difficult to draw because typically the creation of a system will generate both benefit and harm and each set of facts will be different. Moreover, the remedies traditionally used (eg, blocking the transaction or requiring that the parties divest assets) by antitrust authorities in cases of net harm are limited. For this reason, local governments may want to introduce new policies that help ensure consumers gain protection in the event of consolidation, such as insurance products that charge consumers more for high-priced clinicians and health care centers, bundling payments to clinicians and health care organizations to eliminate the incentives of big institutions to simply provide more care, and establishing area-specific price or spending targets.

JAMA: 12 Nov 2013; 310:1964-70
Cutler DM, Scott Morton F
JAMA: 12 Nov 2013; 310:1964-70 | PMID: 24219952
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Abstract

Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer: The ACOSOG Z1071 (Alliance) Clinical Trial.

Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, ... Hunt KK, for the Alliance for Clinical Trials in Oncology
IMPORTANCE Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies. Objective To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer. Design, setting, and patients The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged. MAIN OUTCOMES AND MEASURES The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease. RESULTS Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%). CONCLUSIONS AND RELEVANCE Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00881361.

JAMA: 08 Oct 2013; 310:1455-1461
Boughey JC, Suman VJ, Mittendorf EA, Ahrendt GM, ... Hunt KK, for the Alliance for Clinical Trials in Oncology
JAMA: 08 Oct 2013; 310:1455-1461 | PMID: 24101169
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Abstract

Out-of-Hospital Administration of Intravenous Glucose-Insulin-Potassium in Patients With Suspected Acute Coronary Syndromes: The IMMEDIATE Randomized Controlled Trial.

Selker HP, Beshansky JR, Sheehan PR, Massaro JM, ... Apstein CS, Udelson JE
Context Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration.Objective To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS).Design, Setting, and Participants Randomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS.Intervention Intravenous GIK solution (n = 411) or identical-appearing 5% glucose placebo (n = 460) administered by paramedics in the out-of-hospital setting and continued for 12 hours.Main Outcome Measures The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation.Results There was no significant difference in the rate of progression to MI among patients who received GIK (n = 200; 48.7%) vs those who received placebo (n = 242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66-1.13; P = .28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40-1.29; P = .27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27-0.85; P = .01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40-1.38; P = .34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27-1.49; P = .29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18-0.82; P = .01). Serious adverse events occurred in 6.8% (n = 28) with GIK vs 8.9% (n = 41) with placebo (P = .26).Conclusions Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality.Trial registration clinicaltrials.gov Identifier: NCT00091507.

JAMA: 27 Mar 2012; epub ahead of print
Selker HP, Beshansky JR, Sheehan PR, Massaro JM, ... Apstein CS, Udelson JE
JAMA: 27 Mar 2012; epub ahead of print | PMID: 22452807
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Abstract

Idiopathic short stature: a clinical review.

Cohen LE
IMPORTANCE Approximately 2% of children are defined as having short stature. Deciding when to pursue recombinant human growth hormone therapy to increase adult height is controversial. Objective To review the management of children with idiopathic short stature, including diagnostic evaluation and therapeutic options. EVIDENCE REVIEW Systematic literature search of PubMed, Embase, and the Cochrane Library databases. For height outcome, articles were limited to studies reporting adult height and to systematic reviews. FINDINGS Recombinant human growth hormone therapy of children with idiopathic short stature increases height in some children. The estimated mean gain in adult height is 5.2 cm (2 in). The cost-benefit ratio is controversial. Treatment with growth hormone appears safe in the short term, while data on long-term effects are limited because studies of long-term efficacy were not powered to determine safety. CONCLUSIONS AND RELEVANCE Growth hormone treatment may be considered in some children with idiopathic short stature.

JAMA: 04 May 2014; 311:1787-96
Cohen LE
JAMA: 04 May 2014; 311:1787-96 | PMID: 24794372
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Abstract

Evaluation of Surveillance Bias and the Validity of the Venous Thromboembolism Quality Measure.

Bilimoria KY, Chung J, Ju MH, Haut ER, ... Ko CY, Baker DW
IMPORTANCE Postoperative venous thromboembolism (VTE) rates are widely reported quality metrics soon to be used in pay-for-performance programs. Surveillance bias occurs when some clinicians use imaging studies to detect VTE more frequently than other clinicians. Because they look more, they find more VTE events, paradoxically worsening their hospital\'s VTE quality measure performance. A surveillance bias may influence VTE measurement if (1) greater hospital VTE prophylaxis adherence fails to result in lower measured VTE rates, (2) hospitals with characteristics suggestive of higher quality (eg, more accreditations) have greater VTE prophylaxis adherence rates but worse VTE event rates, and (3) higher hospital VTE imaging utilization use rates are associated with higher measured VTE event rates. Objective To examine whether a surveillance bias influences the validity of reported VTE rates. Design, setting, and participants 2010 Hospital Compare and American Hospital Association data from 2838 hospitals were merged. Next, 2009-2010 Medicare claims data for 954 926 surgical patient discharges from 2786 hospitals who were undergoing 1 of 11 major operations were used to calculate VTE imaging (duplex ultrasonography, chest computed tomography/magnetic resonance imaging, and ventilation-perfusion scans) and VTE event rates. MAIN OUTCOMES AND MEASURES The association between hospital VTE prophylaxis adherence and risk-adjusted VTE event rates was examined. The relationship between a summary score of hospital structural characteristics reflecting quality (hospital size, numbers of accreditations/quality initiatives) and performance on VTE prophylaxis and risk-adjusted VTE measures was examined. Hospital-level VTE event rates were compared across VTE diagnostic imaging rate quartiles and with a quantile regression. RESULTS Greater hospital VTE prophylaxis adherence rates were weakly associated with worse risk-adjusted VTE event rates (r2 = 4.2%; P = .03). Hospitals with increasing structural quality scores had higher VTE prophylaxis adherence rates (93.3% vs 95.5%, lowest vs highest quality quartile; P &lt; .001) but worse risk-adjusted VTE rates (4.8 vs 6.4 per 1000, lowest vs highest quality quartile; P &lt; .001). Mean VTE diagnostic imaging rates ranged from 32 studies per 1000 in the lowest imaging use quartile to 167 per 1000 in the highest quartile (P &lt; .001). Risk-adjusted VTE rates increased significantly with VTE imaging use rates in a stepwise fashion, from 5.0 per 1000 in the lowest quartile to 13.5 per 1000 in the highest quartile (P &lt; .001). CONCLUSIONS AND RELEVANCE Hospitals with higher quality scores had higher VTE prophylaxis rates but worse risk-adjusted VTE rates. Increased hospital VTE event rates were associated with increasing hospital VTE imaging use rates. Surveillance bias limits the usefulness of the VTE quality measure for hospitals working to improve quality and patients seeking to identify a high-quality hospital.

JAMA: 08 Oct 2013; 310:1482-1489
Bilimoria KY, Chung J, Ju MH, Haut ER, ... Ko CY, Baker DW
JAMA: 08 Oct 2013; 310:1482-1489 | PMID: 24100354
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Abstract

Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial.

Green RC, Schneider LS, Amato DA, Beelen AP, ... Zavitz KH,
Context: Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial. Objective: To determine the efficacy, safety, and tolerability of tarenflurbil. Design, setting, and patients: A multicenter, randomized, double-blind, placebo-controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the United States between February 21, 2005, and April 30, 2008. Concomitant treatment with cholinesterase inhibitors or memantine was permitted. Intervention: Tarenflurbil, 800 mg, or placebo, administered twice a day. Main outcome measures: Co-primary efficacy end points were the change from baseline to month 18 in total score on the subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease Cooperative Studies-activities of daily living (ADCS-ADL) scale. Additional prespecified slope analyses explored the possibility of disease modification. Results: Of the 1684 participants randomized, 1649 were included in the analysis, and 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes (difference in change from baseline to month 18 vs placebo, based on least squares means: 0.1 for ADAS-Cog; 95% CI, -0.9 to 1.1; P = .86 and -0.5 for ADCS-ADL; 95% CI, -1.9 to 0.9; P = .48) using an intent-to-treat analysis. No significant differences occurred in the secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections. Conclusion: Tarenflurbil did not slow cognitive decline or the loss of activities of daily living in patients with mild AD. Trial registration: clinicaltrials.gov Identifier: NCT00105547.

JAMA: 16 Dec 2009; 302:2557-64
Green RC, Schneider LS, Amato DA, Beelen AP, ... Zavitz KH,
JAMA: 16 Dec 2009; 302:2557-64 | PMID: 20009055
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Abstract

Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock: The CRISTAL Randomized Trial.

Annane D, Siami S, Jaber S, Martin C, ... Chevret S, for the CRISTAL Investigators
IMPORTANCE Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. Objective To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. Design, setting, and participants A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00318942.

JAMA: 09 Oct 2013; epub ahead of print
Annane D, Siami S, Jaber S, Martin C, ... Chevret S, for the CRISTAL Investigators
JAMA: 09 Oct 2013; epub ahead of print | PMID: 24108515
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Abstract

Immunogenicity of a Monovalent 2009 Influenza A(H1N1) Vaccine in Infants and Children: A Randomized Trial.

Nolan T, McVernon J, Skeljo M, Richmond P, ... Gittleson C, Greenberg M
Context: In the ongoing influenza pandemic, a safe and effective vaccine against 2009 influenza A(H1N1) is needed for infants and children. Objective: To assess the immunogenicity and safety of a 2009 influenza A(H1N1) vaccine in children. Design, setting, and participants: Randomized, observer-blind, age-stratified, parallel group study assessing 2 doses of an inactivated, split-virus 2009 influenza A(H1N1) vaccine in 370 healthy infants and children aged 6 months to less than 9 years living in Australia. Intervention: Intramuscular injection of 15 mug or 30 mug of hemagglutinin antigen dose of monovalent, unadjuvanted 2009 influenza A(H1N1) vaccine in a 2-dose regimen, administered 21 days apart. Main outcome measures: Hemagglutination inhibition assay to estimate the proportion of participants with antibody titers of 1:40 or greater, seroconversion, or a significant antibody titer increase, and factor increase in geometric mean titer. Assessments of solicited adverse events during 7 days and unsolicited adverse events for 21 days after each vaccination. Results: Following the first dose of vaccine, antibody titers of 1:40 or greater were observed in 161 of 174 infants and children in the 15-mug group (92.5%; 95% confidence interval [CI], 87.6%-95.6%) and in 168 of 172 infants and children in the 30-mug group (97.7%; 95% CI, 94.2%-99.1%). Corresponding seroconversion rates were 86.8% (95% CI, 80.9%-91.0%) and 94.2% (95% CI, 89.6%-96.8%), and factor increases in geometric mean titer were 13.6 (95% CI, 11.8-15.6) and 18.3 (95% CI, 15.7-21.4). All participants demonstrated antibody titers of 1:40 or greater after the second vaccine dose. Immune responses were robust regardless of age, baseline serostatus, or seasonal influenza vaccination status. The majority of adverse events were mild to moderate in severity. Conclusion: One 15-mug dose of vaccine was immunogenic in infants and children starting at 6 months of age and vaccine-associated reactions were mild to moderate in severity.Trial registration clinicaltrials.gov Identifier: NCT00940108Published online December 21, 2009 (doi:10.1001/jama.2009.1911).

JAMA: 22 Dec 2009; epub ahead of print
Nolan T, McVernon J, Skeljo M, Richmond P, ... Gittleson C, Greenberg M
JAMA: 22 Dec 2009; epub ahead of print | PMID: 20026597
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Abstract

The familial risk of autism.

Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A
IMPORTANCE Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved. Objective To provide estimates of familial aggregation and heritability of ASD. Design, setting, and participants A population-based cohort including 2 049 973 Swedish children born 1982 through 2006. We identified 37 570 twin pairs, 2 642 064 full sibling pairs, 432 281 maternal and 445 531 paternal half sibling pairs, and 5 799 875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained. MAIN OUTCOMES AND MEASURES The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors. RESULTS In the sample, 14 516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100 000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64). CONCLUSIONS AND RELEVANCE Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.

JAMA: 04 May 2014; 311:1770-7
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A
JAMA: 04 May 2014; 311:1770-7 | PMID: 24794370
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Maternal Body Mass Index and the Risk of Fetal Death, Stillbirth, and Infant Death: A Systematic Review and Meta-analysis.

Aune D, Saugstad OD, Henriksen T, Tonstad S
IMPORTANCE Evidence suggests that maternal obesity increases the risk of fetal death, stillbirth, and infant death; however, the optimal body mass index (BMI) for prevention is not known. Objective To conduct a systematic review and meta-analysis of cohort studies of maternal BMI and risk of fetal death, stillbirth, and infant death. Data sources The PubMed and Embase databases were searched from inception to January 23, 2014. STUDY SELECTION Cohort studies reporting adjusted relative risk (RR) estimates for fetal death, stillbirth, or infant death by at least 3 categories of maternal BMI were included. DATA EXTRACTION Data were extracted by 1 reviewer and checked by the remaining reviewers for accuracy. Summary RRs were estimated using a random-effects model. MAIN OUTCOMES AND MEASURES Fetal death, stillbirth, and neonatal, perinatal, and infant death. RESULTS Thirty eight studies (44 publications) with more than 10 147 fetal deaths, more than 16 274 stillbirths, more than 4311 perinatal deaths, 11 294 neonatal deaths, and 4983 infant deaths were included. The summary RR per 5-unit increase in maternal BMI for fetal death was 1.21 (95% CI, 1.09-1.35; I2 = 77.6%; n = 7 studies); for stillbirth, 1.24 (95% CI, 1.18-1.30; I2 = 80%; n = 18 studies); for perinatal death, 1.16 (95% CI, 1.00-1.35; I2 = 93.7%; n = 11 studies); for neonatal death, 1.15 (95% CI, 1.07-1.23; I2 = 78.5%; n = 12 studies); and for infant death, 1.18 (95% CI, 1.09-1.28; I2 = 79%; n = 4 studies). The test for nonlinearity was significant in all analyses but was most pronounced for fetal death. For women with a BMI of 20 (reference standard for all outcomes), 25, and 30, absolute risks per 10 000 pregnancies for fetal death were 76, 82 (95% CI, 76-88), and 102 (95% CI, 93-112); for stillbirth, 40, 48 (95% CI, 46-51), and 59 (95% CI, 55-63); for perinatal death, 66, 73 (95% CI, 67-81), and 86 (95% CI, 76-98); for neonatal death, 20, 21 (95% CI, 19-23), and 24 (95% CI, 22-27); and for infant death, 33, 37 (95% CI, 34-39), and 43 (95% CI, 40-47), respectively. CONCLUSIONS AND RELEVANCE Even modest increases in maternal BMI were associated with increased risk of fetal death, stillbirth, and neonatal, perinatal, and infant death. Weight management guidelines for women who plan pregnancies should take these findings into consideration to reduce the burden of fetal death, stillbirth, and infant death.

JAMA: 15 Apr 2014; 311:1536-46
Aune D, Saugstad OD, Henriksen T, Tonstad S
JAMA: 15 Apr 2014; 311:1536-46 | PMID: 24737366
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Abstract

Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial.

Mourvillier B, Tubach F, van de Beek D, Garot D, ... Le Tulzo Y, Wolff M
IMPORTANCE Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. Objective To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. Design, setting, and patients An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for &lt;12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00774631.

JAMA: 08 Oct 2013; epub ahead of print
Mourvillier B, Tubach F, van de Beek D, Garot D, ... Le Tulzo Y, Wolff M
JAMA: 08 Oct 2013; epub ahead of print | PMID: 24105303
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Abstract

Increasing demands for quality measurement.

Panzer RJ, Gitomer RS, Greene WH, Webster PR, Landry KR, Riccobono CA
Measurement of health care quality and patient safety is rapidly evolving, in response to long-term needs and more recent efforts to reform the US health system around "value." Development and choice of quality measures is now guided by a national quality strategy and priorities, with a public-private partnership, the National Quality Forum, helping determine the most worthwhile measures for evaluating and rewarding quality and safety of patient care. Yet there remain a number of challenges, including diverse purposes for quality measurement, limited availability of true clinical measures leading to frequent reliance on claims data with its flaws in determining quality, fragmentation of measurement systems with redundancy and conflicting conclusions, few high-quality comprehensive measurement systems and registries, and rapid expansion of required measures with hundreds of measures straining resources. The proliferation of quality measures at the clinician, hospital, and insurer level has created challenges and logistical problems. Recommendations include raising the bar for qualtiy measurements to achieve transformational rather than incremental change in the US quality measurement system, promoting a logical set of measures for the various levels of the health system, leaving room for internal organizational improvement, harmonizing the various national and local quality measurement systems, anchoring on National Quality Forum additions and subtractions of measures to be applied, reducing reliance on and retiring claims-based measures as quickly as possible, promoting comprehensive measurement such as through registries with deep understanding of patient risk factors and outcomes, reducing attention to proprietary report cards, prompt but careful transition to measures from electronic health records, and allocation of sufficient resources to accomplish the goals of an efficient, properly focused measurement system.

JAMA: 12 Nov 2013; 310:1971-80
Panzer RJ, Gitomer RS, Greene WH, Webster PR, Landry KR, Riccobono CA
JAMA: 12 Nov 2013; 310:1971-80 | PMID: 24219953
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Abstract

Trends and Outcomes for Donor Oocyte Cycles in the United States, 2000-2010.

Kawwass JF, Monsour M, Crawford S, Kissin DM, ... Jamieson DJ, for the National ART Surveillance System (NASS) Group
IMPORTANCE The prevalence of oocyte donation for in vitro fertilization (IVF) has increased in the United States, but little information is available regarding maternal or infant outcomes to improve counseling and clinical decision making. ObjectiveS To quantify trends in donor oocyte cycles in the United States and to determine predictors of a good perinatal outcome among IVF cycles using fresh (noncryopreserved) embryos derived from donor oocytes. Design, setting, and participants Analysis of data from the Centers for Disease Control and Prevention\'s National ART Surveillance System, to which fertility centers are mandated to report and which includes data on more than 95% of all IVF cycles performed in the United States. Data from 2000 to 2010 described trends. Data from 2010 determined predictors. MAIN OUTCOMES AND MEASURES Good perinatal outcome, defined as a singleton live-born infant delivered at 37 weeks or later and weighing 2500 g or more. RESULTS From 2000 to 2010, data from 443 clinics (93% of all US fertility centers) were included. The annual number of donor oocyte cycles significantly increased, from 10 801 to 18 306. Among all donor oocyte cycles, an increasing trend was observed from 2000 to 2010 in the proportion of cycles using frozen (vs fresh) embryos (26.7% [95% CI, 25.8%-27.5%] to 40.3% [95% CI, 39.6%-41.1%]) and elective single-embryo transfers (vs transfer of multiple embryos) (0.8% [95% CI, 0.7%-1.0%] to 14.5% [95% CI, 14.0%-15.1%]). Good perinatal outcomes increased from 18.5% (95% CI, 17.7%-19.3%) to 24.4% (95% CI, 23.8%-25.1%) (P &lt; .001 for all listed trends). Mean donor and recipient ages remained stable at 28 (SD, 2.8) years and 41 (SD, 5.3) years, respectively. In 2010, 396 clinics contributed data. For donor oocyte cycles using fresh embryos (n = 9865), 27.5% (95% CI, 26.6%-28.4%) resulted in good perinatal outcome. Transfer of an embryo at day 5 (adjusted odds ratio [OR], 1.17 [95% CI, 1.04-1.32]) and elective single-embryo transfers (adjusted OR, 2.32 [95% CI, 1.92-2.80]) were positively associated with good perinatal outcome; tubal (adjusted OR, 0.72 [95% CI, 0.60-0.86]) or uterine (adjusted OR, 0.74 [95% CI, 0.58-0.94]) factor infertility and non-Hispanic black recipient race/ethnicity (adjusted OR, 0.48 [95% CI, 0.35-0.67]) were associated with decreased odds of good outcome. Recipient age was not associated with likelihood of good perinatal outcome. CONCLUSIONS AND RELEVANCE In the United States from 2000 to 2010, there was an increase in number of donor oocyte cycles, accompanied by an increase in good outcomes. Further studies are needed to understand the mechanisms underlying the factors associated with less successful outcomes.

JAMA: 17 Oct 2013; epub ahead of print
Kawwass JF, Monsour M, Crawford S, Kissin DM, ... Jamieson DJ, for the National ART Surveillance System (NASS) Group
JAMA: 17 Oct 2013; epub ahead of print | PMID: 24135860
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Abstract

Insulin therapy for type 2 diabetes mellitus.

Wallia A, Molitch ME
IMPORTANCE The incidence and prevalence of type 2 diabetes mellitus are increasing. Objective To review currently available insulin therapy, as well as evidence on the use, application, initiation, and intensification of insulin in the outpatient setting. EVIDENCE REVIEW Data sources included PubMed for trials and investigations in type 2 diabetes examining insulin use from January 1998 to April 2014. FINDINGS The hemoglobin A1c target for most patients with type 2 diabetes is 7% but needs to be modified when there is increased risk of hypoglycemia, reduced life expectancy, extensive comorbidities, or reduced resources. Insulin therapy may be considered early or late in the disease course; adverse effects include weight gain and hypoglycemia. Basal insulin can be added to oral hypoglycemic agents (generally stopping sulfonylureas) initially, and later, prandial insulin can be added in a stepwise fashion. Insulin treatment must be individualized, and there are a number of challenges to insulin initiation and intensification. CONCLUSIONS AND RELEVANCE Insulin can help achieve ideal hemoglobin A1c goals for patients with type 2 diabetes. Barriers such as adherence, patient preferences, clinician preferences, and resource allocation must be addressed.

JAMA: 10 Jun 2014; 311:2315-25
Wallia A, Molitch ME
JAMA: 10 Jun 2014; 311:2315-25 | PMID: 24915263
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Abstract

Safety and immunogenicity of tetanus diphtheria and acellular pertussis (tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial.

Munoz FM, Bond NH, Maccato M, Pinell P, ... Goll JB, Baker CJ
IMPORTANCE Maternal immunization with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine could prevent infant pertussis. Objective To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine. Design, setting, and participants Phase 1-2, randomized, double-blind, placebo-controlled, clinical trial conducted from 2008 to 2012. Forty-eight pregnant women aged 18 to 45 years received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks\' gestation, with crossover immunization postpartum. INTERVENTIONS Tdap vaccination at 30 to 32 weeks\' gestation or postpartum. MAIN OUTCOMES AND MEASURES Primary outcomes were maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months. Secondary outcomes were antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months\' postpartum, and in infants at birth, at 2 months, and after the third and fourth doses of DTaP. RESULTS No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%-91.0%]) and 12 (80% [95% CI, 51.9%-95.7%]) pregnant and postpartum women, respectively (P &gt; .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%-54.9%]) and 11 (73.3% [95% CI, 44.9%-92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1-70.1] and 9.1 EU/mL [95% CI, 4.6-17.8], respectively; P &lt; .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1-90.8] and 14.0 EU/mL [95% CI, 7.3-26.9], respectively; P &lt; .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4-29.6] and 5.3 EU/mL [95% CI, 3.0-9.4], respectively; P &lt; .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP. CONCLUSIONS AND RELEVANCE This preliminary assessment did not find an increased risk of adverse events among women who received Tdap vaccine during pregnancy or their infants. For secondary outcomes, maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00707148.

JAMA: 04 May 2014; 311:1760-9
Munoz FM, Bond NH, Maccato M, Pinell P, ... Goll JB, Baker CJ
JAMA: 04 May 2014; 311:1760-9 | PMID: 24794369
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Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults: The LIFE Study Randomized Clinical Trial.

Pahor M, Guralnik JM, Ambrosius WT, Blair S, ... Williamson JD, for the LIFE study investigators
IMPORTANCE In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, setting, and participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. INTERVENTIONS Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. MAIN OUTCOMES AND MEASURES The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. RESULTS Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03).Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). CONCLUSIONS AND RELEVANCE A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01072500.

JAMA: 27 May 2014; epub ahead of print
Pahor M, Guralnik JM, Ambrosius WT, Blair S, ... Williamson JD, for the LIFE study investigators
JAMA: 27 May 2014; epub ahead of print | PMID: 24866862
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Abstract

Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population.

de Lemos JA, Drazner MH, Omland T, Ayers CR, ... Morrow DA, McGuire DK
Context: Detectable levels of cardiac troponin T (cTnT) are strongly associated with structural heart disease and increased risk of death and adverse cardiovascular events; however, cTnT is rarely detectable in the general population using standard assays. ObjectiveS: To determine the prevalence and determinants of detectable cTnT in the population using a new highly sensitive assay and to assess whether cTnT levels measured with the new assay associate with pathological cardiac phenotypes and subsequent mortality. Design, setting, and participants: Cardiac troponin T levels were measured using both the standard and the highly sensitive assays in 3546 individuals aged 30 to 65 years enrolled between 2000 and 2002 in the Dallas Heart Study, a multiethnic, population-based cohort study. Mortality follow-up was complete through 2007. Participants were placed into 5 categories based on cTnT levels. Main outcome measures: Magnetic resonance imaging measurements of cardiac structure and function and mortality through a median of 6.4 (interquartile range, 6.0-6.8) years of follow-up. Results: In Dallas County, the prevalence of detectable cTnT (≥0.003 ng/mL) was 25.0% (95% confidence interval [CI], 22.7%-27.4%) with the highly sensitive assay vs 0.7% (95% CI, 0.3%-1.1%) with the standard assay. Prevalence was 37.1% (95% CI, 33.3%-41.0%) in men vs 12.9% (95% CI, 10.6%-15.2%) in women and 14.0% (95% CI, 11.2%-16.9%) in participants younger than 40 years vs 57.6% (95% CI, 47.0%-68.2%) in those 60 years and older. Prevalence of left ventricular hypertrophy increased from 7.5% (95% CI, 6.4%-8.8%) in the lowest cTnT category (<0.003 ng/mL) to 48.1% (95% CI, 36.7%-59.6%) in the highest (≥0.014 ng/mL) (P < .001); prevalence of left ventricular systolic dysfunction and chronic kidney disease also increased across categories (P < .001 for each). During a median follow-up of 6.4 years, there were 151 total deaths, including 62 cardiovascular disease deaths. All-cause mortality increased from 1.9% (95% CI, 1.5%-2.6%) to 28.4% (95% CI, 21.0%-37.8%) across higher cTnT categories (P < .001). After adjustment for traditional risk factors, C-reactive protein level, chronic kidney disease, and N-terminal pro-brain-type natriuretic peptide level, cTnT category remained independently associated with all-cause mortality (adjusted hazard ratio, 2.8 [95% CI, 1.4-5.2] in the highest category). Adding cTnT categories to the fully adjusted mortality model modestly improved model fit (P = .02) and the integrated discrimination index (0.010 [95% CI, 0.002-0.018]; P = .01). Conclusion: In this population-based cohort, cTnT detected with a highly sensitive assay was associated with structural heart disease and subsequent risk for all-cause mortality.

JAMA: 08 Dec 2010; 304:2503-12
de Lemos JA, Drazner MH, Omland T, Ayers CR, ... Morrow DA, McGuire DK
JAMA: 08 Dec 2010; 304:2503-12 | PMID: 21139111
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Vitamin C Supplementation for Pregnant Smoking Women and Pulmonary Function in Their Newborn Infants: A Randomized Clinical Trial.

McEvoy CT, Schilling D, Clay N, Jackson K, ... Morris CD, Spindel ER
IMPORTANCE Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function. Objective To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo. Design, setting, and participants Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year. INTERVENTIONS Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90). MAIN OUTCOMES AND MEASURES The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed. RESULTS Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) (P &lt; .001 for interaction). CONCLUSIONS AND RELEVANCE Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00632476.

JAMA: 18 May 2014; epub ahead of print
McEvoy CT, Schilling D, Clay N, Jackson K, ... Morris CD, Spindel ER
JAMA: 18 May 2014; epub ahead of print | PMID: 24838476
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Intra-aortic Balloon Counterpulsation and Infarct Size in Patients With Acute Anterior Myocardial Infarction Without Shock: The CRISP AMI Randomized Trial.

Patel MR, Smalling RW, Thiele H, Barnhart HX, ... Perera D, Ohman EM
Context Intra-aortic balloon counterpulsation (IABC) is an adjunct to revascularization in patients with cardiogenic shock and reduces infarct size when placed prior to reperfusion in animal models.Objective To determine if routine IABC placement prior to reperfusion in patients with anterior ST-segment elevation myocardial infarction (STEMI) without shock reduces myocardial infarct size.Design, Setting, and Patients An open, multicenter, randomized controlled trial, the Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) included 337 patients with acute anterior STEMI but without cardiogenic shock at 30 sites in 9 countries from June 2009 through February 2011.Intervention Initiation of IABC before primary percutaneous coronary intervention (PCI) and continuation for at least 12 hours (IABC plus PCI) vs primary PCI alone.Main Outcome Measures Infarct size expressed as a percentage of left ventricular (LV) mass and measured by cardiac magnetic resonance imaging performed 3 to 5 days after PCI. Secondary end points included all-cause death at 6 months and vascular complications and major bleeding at 30 days. Multiple imputations were performed for missing infarct size data.Results The median time from first contact to first coronary device was 77 minutes (interquartile range, 53 to 114 minutes) for the IABC plus PCI group vs 68 minutes (interquartile range, 40 to 100 minutes) for the PCI alone group (P = .04). The mean infarct size was not significantly different between the patients in the IABC plus PCI group and in the PCI alone group (42.1% [95% CI, 38.7% to 45.6%] vs 37.5% [95% CI, 34.3% to 40.8%], respectively; difference of 4.6% [95% CI, -0.2% to 9.4%], P = .06; imputed difference of 4.5% [95% CI, -0.3% to 9.3%], P = .07) and in patients with proximal left anterior descending Thrombolysis in Myocardial Infarction flow scores of 0 or 1 (46.7% [95% CI, 42.8% to 50.6%] vs 42.3% [95% CI, 38.6% to 45.9%], respectively; difference of 4.4% [95% CI, -1.0% to 9.7%], P = .11; imputed difference of 4.8% [95% CI, -0.6% to 10.1%], P = .08). At 30 days, there were no significant differences between the IABC plus PCI group and the PCI alone group for major vascular complications (n = 7 [4.3%; 95% CI, 1.8% to 8.8%] vs n = 2 [1.1%; 95% CI, 0.1% to 4.0%], respectively; P = .09) and major bleeding or transfusions (n = 5 [3.1%; 95% CI, 1.0% to 7.1%] vs n = 3 [1.7%; 95% CI, 0.4% to 4.9%]; P = .49). By 6 months, 3 patients (1.9%; 95% CI, 0.6% to 5.7%) in the IABC plus PCI group and 9 patients (5.2%; 95% CI, 2.7% to 9.7%) in the PCI alone group had died (P = .12).Conclusion Among patients with acute anterior STEMI without shock, IABC plus primary PCI compared with PCI alone did not result in reduced infarct size.Trial registration clinicaltrials.gov Identifier: NCT00833612.

JAMA: 31 Aug 2011; epub ahead of print
Patel MR, Smalling RW, Thiele H, Barnhart HX, ... Perera D, Ohman EM
JAMA: 31 Aug 2011; epub ahead of print | PMID: 21878431
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This program is still in alpha version.