JAMA. 2008;300(3):287-294.
Context Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model. Objective To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1. Design, Setting, and Participants Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital. Intervention Simvastatin or placebo treatment once daily for 12 weeks. Main Outcome Measures Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex. Results No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (β = 0.10; 95% confidence interval [CI], –0.36 to 0.56); cancellation test (β = –0.19; 95% CI, –0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (β = 0.06; 95% CI, –0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (β = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment. Conclusion In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707
JAMA. 2008;299(14):1690-1697.
Context Maintenance therapy for Crohn disease features the use of immunosuppressive drugs, which are associated with an increased risk of infection. Identification of safe and effective maintenance strategies is a priority. Objective To determine whether the oral administration of omega-3 free fatty acids is more effective than placebo for prevention of relapse of Crohn disease. Design, Setting, and Patients Two randomized, double-blind, placebo-controlled studies (Epanova Program in Crohn's Study 1 [EPIC-1] and EPIC-2) conducted between January 2003 and February 2007 at 98 centers in Canada, Europe, Israel, and the United States. Data from 363 and 375 patients with quiescent Crohn disease were evaluated in EPIC-1 and EPIC-2, respectively. Interventions Patients with a Crohn's Disease Activity Index (CDAI) score of less than 150 were randomly assigned to receive either 4 g/d of omega-3 free fatty acids or placebo for up to 58 weeks. No other treatments for Crohn disease were permitted. Main Outcome Measure Clinical relapse, as defined by a CDAI score of 150 points or greater and an increase of more than 70 points from the baseline value, or initiation of treatment for active Crohn disease. Results For EPIC-1, 188 patients were assigned to receive omega-3 free fatty acids and 186 patients to receive placebo. Corresponding numbers for EPIC-2 were 189 and 190 patients, respectively. The rate of relapse at 1 year in EPIC-1 was 31.6% in patients who received omega-3 free fatty acids and 35.7% in those who received placebo (hazard ratio, 0.82; 95% confidence interval, 0.51-1.19; P = .30). Corresponding values for EPIC-2 were 47.8% and 48.8% (hazard ratio, 0.90; 95% confidence interval, 0.67-1.21; P = .48). Serious adverse events were uncommon and mostly related to Crohn disease. Conclusion In these trials, treatment with omega-3 free fatty acids was not effective for the prevention of relapse in Crohn disease. Trial Registration clinicaltrials.gov Identifiers: EPIC-1: NCT00613197, EPIC-2: NCT00074542
JAMA. 2008;299(6):637-645.
Context Low-tidal-volume ventilation reduces mortality in critically ill patients with acute lung injury and acute respiratory distress syndrome. Instituting additional strategies to open collapsed lung tissue may further reduce mortality. Objective To compare an established low-tidal-volume ventilation strategy with an experimental strategy based on the original "open-lung approach," combining low tidal volume, lung recruitment maneuvers, and high positive-end–expiratory pressure. Design and Setting Randomized controlled trial with concealed allocation and blinded data analysis conducted between August 2000 and March 2006 in 30 intensive care units in Canada, Australia, and Saudi Arabia. Patients Nine hundred eighty-three consecutive patients with acute lung injury and a ratio of arterial oxygen tension to inspired oxygen fraction not exceeding 250. Interventions The control strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau airway pressures not exceeding 30 cm H2O, and conventional levels of positive end-expiratory pressure (n = 508). The experimental strategy included target tidal volumes of 6 mL/kg of predicted body weight, plateau pressures not exceeding 40 cm H2O, recruitment maneuvers, and higher positive end-expiratory pressures (n = 475). Main Outcome Measure All-cause hospital mortality. Results Eighty-five percent of the 983 study patients met criteria for acute respiratory distress syndrome at enrollment. Tidal volumes remained similar in the 2 groups, and mean positive end-expiratory pressures were 14.6 (SD, 3.4) cm H2O in the experimental group vs 9.8 (SD, 2.7) cm H2O among controls during the first 72 hours (P < .001). All-cause hospital mortality rates were 36.4% and 40.4%, respectively (relative risk [RR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .19). Barotrauma rates were 11.2% and 9.1% (RR, 1.21; 95% CI, 0.83-1.75; P = .33). The experimental group had lower rates of refractory hypoxemia (4.6% vs 10.2%; RR, 0.54; 95% CI, 0.34-0.86; P = .01), death with refractory hypoxemia (4.2% vs 8.9%; RR, 0.56; 95% CI, 0.34-0.93; P = .03), and previously defined eligible use of rescue therapies (5.1% vs 9.3%; RR, 0.61; 95% CI, 0.38-0.99; P = .045). Conclusions For patients with acute lung injury and acute respiratory distress syndrome, a multifaceted protocolized ventilation strategy designed to recruit and open the lung resulted in no significant difference in all-cause hospital mortality or barotrauma compared with an established low-tidal-volume protocolized ventilation strategy. This "open-lung" strategy did appear to improve secondary end points related to hypoxemia and use of rescue therapies. Trial Registration clinicaltrials.gov Identifier: NCT00182195
JAMA. 2008;300(5):540-549.
Context Studies of factors associated with acquiring human immunodeficiency virus (HIV) are often based on prevalence data that might not reflect recent infections. Objective To determine demographic, biological, and behavioral factors for recent HIV infection in Uganda. Design and Setting Nationally representative household survey of cross-sectional design conducted in Uganda from August 2004 through January 2005; data were analyzed until November 2007. Participants There were 11 454 women and 9905 men aged 15 to 59 years who were eligible. Questionnaires were completed for 10 826 women (95%) and 8830 men (89%); of those interviewed, blood specimens were collected for 10 227 women (94%) and 8298 men (94%). Main Outcome Measure Specimens seropositive for HIV were tested with the BED IgG capture-based enzyme immunosorbent assay to identify recent seroconversions (median, 155 days) using normalized optical density of 0.8 and adjustments. Results Of the 1023 HIV infections with BED results, 172 (17%) tested as recent. In multivariate analysis, risk factors associated with recent HIV infection included female sex (adjusted odds ratio [aOR], 2.4; 95% confidence interval [CI], 1.1-5.2); current marital status (widowed vs never married, aOR, 6.1; 95% CI, 2.8-13.3; divorced vs never married, aOR, 3.0; 95% CI, 1.5-6.1); geographic region (north central Uganda vs central Uganda/Kampala, aOR, 2.6; 95% CI, 1.7-4.1); number of sex partners in past year (2 compared with none; aOR, 2.9; 95% CI, 1.6-5.5); herpes simplex virus type 2 infection (aOR, 3.9; 95% CI, 2.6-5.8); report of a sexually transmitted disease in the past year (aOR, 1.7; 95% CI, 1.2-2.4); and being an uncircumcised man (aOR, 2.5; 95% CI, 1.1-5.3). Among married participants, recent HIV infection was associated with never using condoms with partners outside of marriage (aOR, 3.2; 95% CI, 1.7-6.1) compared with individuals having no outside partners. The risk of incident HIV infection for married individuals who used condoms with at least 1 outside partner was similar to that of those who did not have any partners outside of marriage (aOR, 1.0; 95% CI, 0.3-2.7). Conclusion A survey of individuals in Uganda who were tested with an HIV assay used to establish recent infection identified risk factors, which offers opportunities for prevention initiatives.
JAMA. 2008;300(5):530-539.
Context Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described. Objective To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy. Design, Setting, and Participants Cohort analysis of prospectively collected routine clinical data in a community–based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006. Interventions Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine. Main Outcome Measures Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed. Results The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7). Conclusion In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.
JAMA. 2008;299(7):793-805.
Context Acute renal failure requiring dialytic support is associated with a high risk of mortality and substantial morbidity. Objectives To summarize current evidence guiding provision of dialysis for patients with acute renal failure, to make recommendations for management, and to identify areas in which additional research is needed. Data Sources Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and All EBM Reviews through October 2007. Study Selection Randomized controlled trials (RCTs) and prospective cohort studies studying dialytic support in adults with acute renal failure that reported the incidence of clinical outcomes such as mortality, length of stay, need for chronic dialysis, or development of hypotension. Data Extraction Quality was independently assessed by 2 reviewers using the Jadad score (RCTs) and the Downs and Black checklist (cohort studies). A single reviewer extracted data, which were independently verified by a second reviewer. Results of RCTs were pooled using a random-effects model. Data Synthesis From 173 retrieved articles, 30 RCTs and 8 prospective cohort studies were eligible. No conclusions could be drawn about optimal indications for or timing of renal replacement. Available data comparing continuous renal replacement therapy (CRRT) with intermittent hemodialysis demonstrated no clinically relevant difference between modalities, including for all-cause mortality (relative risk [RR], 1.10; 95% confidence interval [CI], 0.99-1.23; I2 = 0%) or for the requirement for chronic dialysis treatment in survivors (RR, 0.91; 95% CI, 0.56-1.49; I2 = 0%). For patients treated with CRRT, limited data suggest that bicarbonate may be preferable to other forms of dialysate alkali and that citrate infusion may be an alternative to systemic anticoagulation in patients at high risk of bleeding. Among patients treated with continuous venovenous hemofiltration (CVVHF), the risk of death was lower at doses of 35 mL/kg per hour (RR of death compared with doses of 20 mL/kg per hour, 0.74; 95% CI, 0.63-0.88). The use of unsubstituted cellulosic membranes should be avoided in intermittent hemodialysis (RR of death compared with biocompatible membranes, 1.23; 95% CI, 1.01-1.50). Conclusions Based on current data, intermittent hemodialysis and CRRT appear to lead to similar clinical outcomes for patients with ARF. If CVVHF is used, a dose of 35 mL/kg per hour should be provided. Given the paucity of good-quality evidence in this important area, additional large randomized trials are needed to evaluate clinically important outcomes.
JAMA. 1998;279:1094-1099.
Objective.— To review the validity of the clinical assessment and diagnostic tests in patients with suspected deep vein thrombosis (DVT). Methods.— A comprehensive review of the literature was conducted by searching MEDLINE from 1966 to April 1997. Results.— Individual symptoms and signs alone do not reliably predict which patients have DVT. Overall, the diagnostic properties of the clinical examination are poor; the sensitivity of the clinical examination ranges from 60% to 96%, and the specificity ranges from 20% to 72%. However, using specific combinations of risk factors, symptoms, and physical signs for DVT, clinicians can reliably stratify patients with suspected DVT into low, moderate, or high pretest probability categories of actually suffering from DVT. This stratification process in combination with noninvasive testing, such as compression ultrasonography, simplifies the management strategies for patients with suspected DVT. Conclusions.— Use of a clinical prediction guide that includes specific factors from both the history and physical examination in combination with noninvasive tests simplifies management strategies for patients with suspected DVT.
JAMA. 2008;299(23):2777-2788.
Context The importance of the cholesteryl ester transfer protein (CETP) pathway in coronary disease is uncertain. Study of CETP genotypes can help better understand the relevance of this pathway to lipid metabolism and disease risk. Objective To assess associations of CETP genotypes with CETP phenotypes, lipid levels, and coronary risk. Data Sources Studies published between January 1970 and January 2008 were identified through computer-based and manual searches using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database. Previously unreported studies were sought through correspondence with investigators. Study Selection Relevant studies related principally to 3 common (TaqIB [rs708272], I405V [rs5882], and –629C>A [rs1800775]) and 3 uncommon (D442G [rs2303790], –631C>A [rs1800776], and R451Q [rs1800777]) CETP polymorphisms. Data Extraction Information on CETP genotypes, CETP phenotypes, lipid levels, coronary disease, and study characteristics was abstracted from publications, supplied by investigators, or both. Results Ninety-two studies had data on CETP phenotypes, lipid levels, or both in 113 833 healthy participants, and 46 studies had data on 27 196 coronary cases and 55 338 controls. For each A allele inherited, individuals with the TaqIB polymorphism had lower mean CETP mass (–9.7%; 95% confidence interval [CI], –11.7% to –7.8%), lower mean CETP activity (–8.6%; 95% CI, –13.0% to –4.1%), higher mean high-density lipoprotein cholesterol (HDL-C) concentrations (4.5%; 95% CI, 3.8%-5.2%), and higher mean apolipoprotein A-I concentrations (2.4%; 95% CI, 1.6%-3.2%). The pattern of findings was very similar with the I405V and –629C>A polymorphisms. The combined per-allele odds ratios (ORs) for coronary disease were 0.95 (95% CI, 0.92-0.99) for TaqIB, 0.94 (95% CI, 0.89-1.00) for I405V, and 0.95 (95% CI, 0.91-1.00) for –629C>A. Conclusions Three CETP genotypes that are associated with moderate inhibition of CETP activity (and, therefore, modestly higher HDL-C levels) show weakly inverse associations with coronary risk. The ORs for coronary disease were compatible with the expected reductions in risk for equivalent increases in HDL-C concentration in available prospective studies.
JAMA. 2008;300(1):71-80.
Context Although an invasive strategy is frequently used in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. Objective To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. Data Sources Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. Study Selection Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. Data Extraction The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. Data Synthesis Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01; 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67; 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77; 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94; 95% CI, 0.61-1.44; P for interaction = .36) and was associated with a nonsignificant 35% higher odds of death or MI (OR, 1.35; 95% CI, 0.78-2.35; P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.67) if biomarker-positive and 0.72 (95% CI, 0.51-1.01) if biomarker-negative (P for interaction = .09). Conclusions In NSTE ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.
JAMA. 2007;298(22):2634-2643.
Context Thiazolidinediones (TZDs), used to treat type 2 diabetes, are associated with an excess risk of congestive heart failure and possibly acute myocardial infarction. However, the association between TZD use and cardiovascular events has not been adequately evaluated on a population level. Objective To explore the association between TZD therapy and congestive heart failure, acute myocardial infarction, and mortality compared with treatment with other oral hypoglycemic agents. Design, Setting, and Patients Nested case-control analysis of a retrospective cohort study using health care databases in Ontario. We included diabetes patients aged 66 years or older treated with at least 1 oral hypoglycemic agent between 2002 and 2005 (N = 159 026) and followed them up until March 31, 2006. Main Outcome Measures The primary outcome consisted of an emergency department visit or hospitalization for congestive heart failure; secondary outcomes were an emergency department visit or hospitalization for acute myocardial infarction and all-cause mortality. The risks of these events were compared between persons treated with TZDs (rosiglitazone and pioglitazone) and other oral hypoglycemic agent combinations, after matching and adjusting for prognostic factors. Results During a median follow-up of 3.8 years, 12 491 patients (7.9%) had a hospital visit for congestive heart failure, 12 578 (7.9%) had a visit for acute myocardial infarction, and 30 265 (19%) died. Current treatment with TZD monotherapy was associated with a significantly increased risk of congestive heart failure (78 cases; adjusted rate ratio [RR], 1.60; 95% confidence interval [CI], 1.21-2.10; P < .001), acute myocardial infarction (65 cases; RR, 1.40; 95% CI, 1.05-1.86; P = .02), and death (102 cases; RR, 1.29; 95% CI, 1.02-1.62; P = .03) compared with other oral hypoglycemic agent combination therapies (3478 congestive heart failure cases, 3695 acute myocardial infarction cases, and 5529 deaths). The increased risk of congestive heart failure, acute myocardial infarction, and mortality associated with TZD use appeared limited to rosiglitazone. Conclusion In this population-based study of older patients with diabetes, TZD treatment, primarily with rosiglitazone, was associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments.
JAMA. 2008;300(10):1181-1196.
Context The increasing use of Internet-based learning in health professions education may be informed by a timely, comprehensive synthesis of evidence of effectiveness. Objectives To summarize the effect of Internet-based instruction for health professions learners compared with no intervention and with non-Internet interventions. Data Sources Systematic search of MEDLINE, Scopus, CINAHL, EMBASE, ERIC, TimeLit, Web of Science, Dissertation Abstracts, and the University of Toronto Research and Development Resource Base from 1990 through 2007. Study Selection Studies in any language quantifying the association of Internet-based instruction and educational outcomes for practicing and student physicians, nurses, pharmacists, dentists, and other health care professionals compared with a no-intervention or non-Internet control group or a preintervention assessment. Data Extraction Two reviewers independently evaluated study quality and abstracted information including characteristics of learners, learning setting, and intervention (including level of interactivity, practice exercises, online discussion, and duration). Data Synthesis There were 201 eligible studies. Heterogeneity in results across studies was large (I2 79%) in all analyses. Effect sizes were pooled using a random effects model. The pooled effect size in comparison to no intervention favored Internet-based interventions and was 1.00 (95% confidence interval [CI], 0.90-1.10; P < .001; n = 126 studies) for knowledge outcomes, 0.85 (95% CI, 0.49-1.20; P < .001; n = 16) for skills, and 0.82 (95% CI, 0.63-1.02; P < .001; n = 32) for learner behaviors and patient effects. Compared with non-Internet formats, the pooled effect sizes (positive numbers favoring Internet) were 0.10 (95% CI, –0.12 to 0.32; P = .37; n = 43) for satisfaction, 0.12 (95% CI, 0.003 to 0.24; P = .045; n = 63) for knowledge, 0.09 (95% CI, –0.26 to 0.44; P = .61; n = 12) for skills, and 0.51 (95% CI, –0.24 to 1.25; P = .18; n = 6) for behaviors or patient effects. No important treatment-subgroup interactions were identified. Conclusions Internet-based learning is associated with large positive effects compared with no intervention. In contrast, effects compared with non-Internet instructional methods are heterogeneous and generally small, suggesting effectiveness similar to traditional methods. Future research should directly compare different Internet-based interventions.
JAMA. 2008;300(15):1784-1792.
Context Amiodarone effectively suppresses atrial fibrillation but causes many adverse events. Objective To compare major events in patients randomized to receive episodic amiodarone treatment with those who received continuous amiodarone treatment while still aiming to prevent atrial fibrillation. Design, Setting, and Participants A randomized trial of 209 ambulatory patients with recurrent symptomatic persistent atrial fibrillation, conducted from December 2002 through March 2007 at 7 Dutch medical centers. Intervention Patients were randomly assigned to receive either episodic or continuous amiodarone treatment after electrical cardioversion following amiodarone loading. Episodic amiodarone treatment was discontinued after a month of sinus rhythm and reinitiated if atrial fibrillation relapsed (1 month peri–electrical cardioversion). In the continuous treatment group amiodarone was maintained throughout. Main Outcome Measures The primary end point was a composite of amiodarone and underlying heart disease–related major events. The secondary end points were all-cause mortality and cardiovascular hospitalizations. Results After a median follow-up of 2.1 years (range, 0.4-2.5 years), 51 (48%) of those receiving episodic treatment vs 64 (62%) receiving continuous treatment had sinus rhythm (P = .05). There were 85 atrial fibrillation recurrences (80%) among the episodic treatment group vs 56 (54%) in the continuous treatment group (P < .001). No significant difference existed in the incidence of the primary composite end point between each group (37 [35%] episodic vs 34 [33%] continuous; incidence rate difference, 0.2; 95% confidence interval [CI], –10.2 to 10.6). However, there were nonstatistically significant differences in the incidence of amiodarone-related major events (20 [19%] episodic vs 25 [24%] continuous; incidence rate difference, –2.0; 95% CI, –8.7 to 4.6) and underlying heart disease–related major events (17 [16%] episodic vs 9 [9%] continuous; incidence rate difference, 3.6; 95% CI, –1.6 to 8.7). All-cause mortality and cardiovascular hospitalizations were higher among those receiving episodic treatment (56 [53%] vs 35 [34%], P = .02). Conclusions In this study population, there was no difference in the composite of amiodarone and cardiac major adverse events between groups. However, patients receiving episodic treatment had a significantly increased rate of atrial fibrillation recurrence and a significantly higher rate of all-cause mortality and cardiovascular hospitalizations. Trial Registration clinicaltrials.gov Identifier: NCT00392431
JAMA. 2007;298(21):2497-2506.
Context At 30-day follow-up, patients with moderate- and high-risk acute coronary syndromes (ACS) undergoing early invasive treatment in the ACUITY trial with bivalirudin monotherapy vs heparin plus glycoprotein (GP) IIb/IIIa inhibitors had noninferior rates of adverse ischemic events with reduced rates of major bleeding. Deferred upstream use of GP IIb/IIIa inhibitors for selective administration to patients undergoing percutaneous coronary intervention (PCI) resulted in a significant reduction in major bleeding, although a small increase in composite ischemia could not be excluded. Objective To determine 1-year ischemic outcomes for patients in the ACUITY trial. Design, Setting, and Patients A prospective, randomized, open-label trial with 1-year clinical follow-up at 450 academic and community-based institutions in 17 countries. A total of 13 819 patients with moderate- and high-risk ACS undergoing invasive treatment were enrolled between August 23, 2003, and December 5, 2005. Interventions Patients were assigned to heparin plus GP IIb/IIIa inhibitors (n = 4603), bivalirudin plus GP IIb/IIIa inhibitors (n = 4604), or bivalirudin monotherapy (n = 4612). Of these patients, 4605 were assigned to routine upstream GP IIb/IIIa administration and 4602 were deferred to selective GP IIb/IIIa inhibitor administration. Main Outcome Measure Composite ischemia (death, myocardial infarction, or unplanned revascularization for ischemia) at 1 year. Results Composite ischemia at 1 year occurred in 15.4% of patients assigned to heparin plus GP IIb/IIIa inhibitors and 16.0% assigned to bivalirudin plus GP IIb/IIIa inhibitors (compared with heparin plus GP IIb/IIIa inhibitors, HR, 1.05; 95% CI, 0.95-1.16; P = .35), and 16.2% assigned to bivalirudin monotherapy (HR, 1.06; 95% CI, 0.95-1.17; P = .29). Mortality at 1 year occurred in an estimated 3.9% of patients assigned to heparin plus GP IIb/IIIa inhibitors, 3.9% assigned to bivalirudin plus GP IIb/IIIa inhibitors (HR, 0.99; 95% CI, 0.80-1.22; P = .92), and 3.8% assigned to bivalirudin monotherapy (HR, 0.96; 95% CI, 0.77-1.18; P = .67). Composite ischemia occurred in 16.3% of patients assigned to deferred use compared with 15.2% of patients assigned to upstream administration (HR, 1.08; 95% CI, 0.97-1.20; P = .15). Conclusions At 1 year, no statistically significant difference in rates of composite ischemia or mortality among patients with moderate- and high-risk ACS undergoing invasive treatment with the 3 therapies was found. There was no statistically significant difference in the rates of composite ischemia between patients receiving routine upstream administration of GP IIb/IIIa inhibitors vs deferring their use for patients undergoing PCI. Trial Registration clinicaltrials.gov Identifier: NCT00093158
JAMA. 2007;298(24):2895-2904.
Context Urinary tract infection (UTI) is a frequently occurring pediatric illness that, if left untreated, can lead to permanent renal injury. Accordingly, accurate diagnosis of UTI is important. Objective To review the diagnostic accuracy of symptoms and signs for the diagnosis of UTI in infants and children. Data Sources A search of MEDLINE and EMBASE databases was conducted for articles published between 1966 and October 2007, as well as a manual review of bibliographies of all articles meeting inclusion criteria, 1 previously published systematic review, 3 clinical skills textbooks, and 2 experts in the field, yielding 6988 potentially relevant articles. Study Selection Studies were included if they contained data on signs or symptoms of UTI in children through age 18 years. Of 337 articles examined, 12 met all inclusion criteria. Data Extraction Two evaluators independently reviewed, rated, and abstracted data from each article. Data Synthesis In infants with fever, history of a previous UTI (likelihood ratio [LR] range, 2.3-2.9), temperature higher than 40°C (LR range, 3.2-3.3), and suprapubic tenderness (LR, 4.4; 95% confidence interval [CI], 1.6-12.4) were the findings most useful for identifying those with a UTI. Among male infants, lack of circumcision increased the likelihood of a UTI (summary LR, 2.8; 95% CI, 1.9-4.3); and the presence of circumcision was the only finding with an LR of less than 0.5 (summary LR, 0.33; 95% CI, 0.18-0.63). Combinations of findings were more useful than individual findings in identifying infants with a UTI (for temperature >39°C for >48 hours without another potential source for fever on examination, the LR for all findings present was 4.0; 95% CI, 1.2-13.0; and for temperature <39°C with another source for fever, the LR was 0.37; 95% CI, 0.16-0.85). In verbal children, abdominal pain (LR, 6.3; 95% CI, 2.5-16.0), back pain (LR, 3.6; 95% CI, 2.1-6.1), dysuria, frequency, or both (LR range, 2.2-2.8), and new-onset urinary incontinence (LR, 4.6; 95% CI, 2.8-7.6) increased the likelihood of a UTI. Conclusions Although individual signs and symptoms were helpful in the diagnosis of a UTI, they were not sufficiently accurate to definitively diagnose UTIs. Combination of findings can identify infants with a low likelihood of a UTI.
JAMA. 2008;300(6):676-690.
Context Liberia's wars since 1989 have cost tens of thousands of lives and left many people mentally and physically traumatized. Objectives To assess the prevalence and impact of war-related psychosocial trauma, including information on participation in the Liberian civil wars, exposure to sexual violence, social functioning, and mental health. Design, Setting, and Participants A cross-sectional, population-based, multistage random cluster survey of 1666 adults aged 18 years or older using structured interviews and questionnaires, conducted during a 3-week period in May 2008 in Liberia. Main Outcome Measures Symptoms of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), social functioning, exposure to sexual violence, and health and mental health needs among Liberian adults who witnessed or participated in the conflicts during the last 2 decades. Results In the Liberian adult household–based population, 40% (95% confidence interval [CI], 36%-45%; n = 672/1659) met symptom criteria for MDD, 44% (95% CI, 38%-49%; n = 718/1661) met symptom criteria for PTSD, and 8% (95% CI, 5%-10%; n = 133/1666) met criteria for social dysfunction. Thirty-three percent of respondents (549/1666) reported having served time with fighting forces, and 33.2% of former combatant respondents (182/549) were female. Former combatants experienced higher rates of exposure to sexual violence than noncombatants: among females, 42.3% (95% CI, 35.4%-49.1%) vs 9.2% (95% CI, 6.7%-11.7%), respectively; among males, 32.6% (95% CI, 27.6%-37.6%) vs 7.4% (95% CI, 4.5%-10.4%). The rates of symptoms of PTSD, MDD, and suicidal ideation were higher among former combatants than noncombatants and among those who experienced sexual violence vs those who did not. The prevalence of PTSD symptoms among female former combatants who experienced sexual violence (74%; 95% CI, 63%-84%) was higher than among those who did not experience sexual violence (44%; 95% CI, 33%-53%). The prevalence of PTSD symptoms among male former combatants who experienced sexual violence was higher (81%; 95% CI, 74%-87%) than among male former combatants who did not experience sexual violence (46%; 95% CI, 39%-52%). Male former combatants who experienced sexual violence also reported higher rates of symptoms of depression and suicidal ideation. Both former combatants and noncombatants experienced inadequate access to health care (33.0% [95% CI, 22.6%-43.4%] and 30.1% [95% CI, 18.7%-41.6%], respectively). Conclusions Former combatants in Liberia were not exclusively male. Both female and male former combatants who experienced sexual violence had worse mental health outcomes than noncombatants and other former combatants who did not experience exposure to sexual violence.
JAMA. 2008;299(16):1903-1913.
Context A thin, cobalt-chromium stent eluting the antiproliferative agent everolimus from a nonadhesive, durable fluoropolymer has shown promise in preliminary studies in improving clinical and angiographic outcomes in patients with coronary artery disease. Objective To evaluate the safety and efficacy of an everolimus-eluting stent compared with a widely used paclitaxel-eluting stent. Design, Setting, and Patients The SPIRIT III trial, a prospective, randomized, single-blind, controlled trial enrolling patients at 65 academic and community-based US institutions between June 22, 2005, and March 15, 2006. Patients were 1002 men and women undergoing percutaneous coronary intervention in lesions 28 mm or less in length and with reference vessel diameter between 2.5 and 3.75 mm. Angiographic follow-up was prespecified at 8 months in 564 patients and completed in 436 patients. Clinical follow-up was performed at 1, 6, 9, and 12 months. Interventions Patients were randomized 2:1 to receive the everolimus-eluting stent (n = 669) or the paclitaxel-eluting stent (n = 333). Main Outcome Measures The primary end point was noninferiority or superiority of angiographic in-segment late loss. The major secondary end point was noninferiority assessment of target vessel failure events (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months. An additional secondary end point was evaluation of major adverse cardiac events (cardiac death, myocardial infarction, or target lesion revascularization) at 9 and 12 months. Results Angiographic in-segment late loss was significantly less in the everolimus-eluting stent group compared with the paclitaxel group (mean, 0.14 [SD, 0.41] mm vs 0.28 [SD, 0.48] mm; difference, –0.14 [95% CI, –0.23 to –0.05]; P .004). The everolimus stent was noninferior to the paclitaxel stent for target vessel failure at 9 months (7.2% vs 9.0%, respectively; difference, –1.9% [95% CI, –5.6% to 1.8%]; relative risk, 0.79 [95% CI, 0.51 to 1.23]; P < .001). The everolimus stent compared with the paclitaxel stent resulted in significant reductions in composite major adverse cardiac events both at 9 months (4.6% vs 8.1%; relative risk, 0.56 [95% CI, 0.34 to 0.94]; P = .03) and at 1 year (6.0% vs 10.3%; relative risk, 0.58 [95% CI, 0.37 to 0.90]; P = .02), due to fewer myocardial infarctions and target lesion revascularization procedures. Conclusions In this large-scale, prospective randomized trial, an everolimus-eluting stent compared with a paclitaxel-eluting stent resulted in reduced angiographic late loss, noninferior rates of target vessel failure, and fewer major adverse cardiac events during 1 year of follow-up. Trial Registration clinicaltrials.gov Identifier: NCT00180479
JAMA. 2006;296:2441-2450.
Context Lumbar diskectomy is the most common surgical procedure performed for back and leg symptoms in US patients, but the efficacy of the procedure relative to nonoperative care remains controversial. Objective To assess the efficacy of surgery for lumbar intervertebral disk herniation. Design, Setting, and Patients The Spine Patient Outcomes Research Trial, a randomized clinical trial enrolling patients between March 2000 and November 2004 from 13 multidisciplinary spine clinics in 11 US states. Patients were 501 surgical candidates (mean age, 42 years; 42% women) with imaging-confirmed lumbar intervertebral disk herniation and persistent signs and symptoms of radiculopathy for at least 6 weeks. Interventions Standard open diskectomy vs nonoperative treatment individualized to the patient. Main Outcome Measures Primary outcomes were changes from baseline for the Medical Outcomes Study 36-item Short-Form Health Survey bodily pain and physical function scales and the modified Oswestry Disability Index (American Academy of Orthopaedic Surgeons MODEMS version) at 6 weeks, 3 months, 6 months, and 1 and 2 years from enrollment. Secondary outcomes included sciatica severity as measured by the Sciatica Bothersomeness Index, satisfaction with symptoms, self-reported improvement, and employment status. Results Adherence to assigned treatment was limited: 50% of patients assigned to surgery received surgery within 3 months of enrollment, while 30% of those assigned to nonoperative treatment received surgery in the same period. Intent-to-treat analyses demonstrated substantial improvements for all primary and secondary outcomes in both treatment groups. Between-group differences in improvements were consistently in favor of surgery for all periods but were small and not statistically significant for the primary outcomes. Conclusions Patients in both the surgery and the nonoperative treatment groups improved substantially over a 2-year period. Because of the large numbers of patients who crossed over in both directions, conclusions about the superiority or equivalence of the treatments are not warranted based on the intent-to-treat analysis. Trial Registration clinicaltrials.gov Identifier: NCT00000410
JAMA. 2008;300(5):550-554.
Context Highly active antiretroviral therapy (HAART) is often withheld from injection drug users (IDUs) infected with the human immunodeficiency virus (HIV) based on the belief that their unstable lifestyles may predetermine a markedly inferior outcome with HAART. However, long-term evaluations of HIV treatment outcomes among IDUs in comparison with other risk groups are not available. Objective To compare survival rates among HIV-infected patients initiating HAART with and without a history of injection drug use. Design, Setting, and Patients Population-based, prospective cohort study (HAART Observational Medical Evaluation and Research [HOMER]) of 3116 antiretroviral-naive HIV-infected patients in a province-wide HIV/AIDS treatment program in British Columbia, Canada. Of the 3116 patients, 915 were IDUs (29.4%), 579 were female (18.6%), and the median age was 39.4 years (interquartile range, 33.3-46.4 years). Treatment with HAART was initiated between August 1, 1996, and June 30, 2006. The median duration of follow-up was 5.3 years (interquartile range, 2.8-8.3 years) for IDUs and 4.3 years (interquartile range, 2.0-7.6 years) for non-IDUs. Patients were followed up until June 30, 2007. Data were analyzed between November 1, 2007, and May 26, 2008. Main Outcome Measure All-cause mortality. Results Overall, 622 individuals died (20.0%) during the study period (232 IDUs and 390 non-IDUs), for a crude mortality rate of 20.0% (95% confidence interval [CI], 18.4%-21.5%). At 84 months after the initiation of HAART, the product limit estimate of the cumulative all-cause mortality rate was similar between the 915 IDUs (26.5%; 95% CI, 23.2%-29.8%) and 2201 non-IDUs (21.6%; 95% CI, 16.9%-26.2%) (Wilcoxon P = .47). In multivariate time-updated Cox regression, the hazard ratio of mortality was similar between IDUs and non-IDUs (1.09; 95% CI, 0.92-1.29). Conclusion In this study population, injection drug use was not associated with decreased survival among HIV-infected patients initiating HAART.
JAMA. 2008;299(20):2413-2422.
Context Based on concerns about the risk of infection, the jugular site is often preferred over the femoral site for short-term dialysis vascular access. Objective To determine whether jugular catheterization decreases the risk of nosocomial complications compared with femoral catheterization. Design, Setting, and Patients A concealed, randomized, multicenter, evaluator-blinded, parallel-group trial (the Cathedia Study) of 750 patients from a network of 9 tertiary care university medical centers and 3 general hospitals in France conducted between May 2004 and May 2007. The severely ill, bed-bound adults had a body mass index (BMI) of less than 45 and required a first catheter insertion for renal replacement therapy. Intervention Patients were randomized to receive jugular or femoral vein catheterization by operators experienced in placement at both sites. Main Outcome Measures Rates of infectious complications, defined as catheter colonization on removal (primary end point), and catheter-related bloodstream infection. Results Patient and catheter characteristics, including duration of catheterization, were similar in both groups. More hematomas occurred in the jugular group than in the femoral group (13/366 patients [3.6%] vs 4/370 patients [1.1%], respectively; P = .03). The risk of catheter colonization at removal did not differ significantly between the femoral and jugular groups (incidence of 40.8 vs 35.7 per 1000 catheter-days; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.62-1.16; P = .31). A prespecified subgroup analysis demonstrated significant qualitative heterogeneity by BMI (P for the interaction term < .001). Jugular catheterization significantly increased incidence of catheter colonization vs femoral catheterization (45.4 vs 23.7 per 1000 catheter-days; HR, 2.10; 95% CI, 1.13-3.91; P = .017) in the lowest tercile (BMI <24.2), whereas jugular catheterization significantly decreased this incidence (24.5 vs 50.9 per 1000 catheter-days; HR, 0.40; 95% CI, 0.23-0.69; P < .001) in the highest tercile (BMI >28.4). The rate of catheter-related bloodstream infection was similar in both groups (2.3 vs 1.5 per 1000 catheter-days, respectively; P = .42). Conclusion Jugular venous catheterization access does not appear to reduce the risk of infection compared with femoral access, except among adults with a high BMI, and may have a higher risk of hematoma. Trial Registration clinicaltrials.gov Identifier: NCT00277888
JAMA. 2008;300(14):1653-1659.
Context Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. Objective To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. Design, Setting, and Patients A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. Main Outcome Measure Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. Results Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, –1.4% to 0.8%). Conclusion The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. Trial Registration clinicaltrials.gov Identifier: NCT00353093