Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial

Context  Despite many therapeutic advances, mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) remains high. The role of additional antithrombotic agents is unclear, especially among patients not receiving reperfusion therapy. Objective  To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initiated early and given for up to 8 days vs usual care (placebo in those in whom unfractionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI. Design, Setting, and Participants  Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12 092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment. Main Outcome Measures  Composite of death or reinfarction at 30 days (primary) with secondary assessments at 9 days and at final follow-up (3 or 6 months). Results  Death or reinfarction at 30 days was significantly reduced from 677 (11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); absolute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73-0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P = .008). Mortality was significantly reduced throughout the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P = .08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P = .008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days. Conclusion  In patients with STEMI, particularly those not undergoing primary percutaneous coronary intervention, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes. Trial Registration  ClinicalTrials.gov Identifier NCT00064428      

Prophylactic Oral Amiodarone for the Prevention of Arrhythmias that Begin Early After Revascularization, Valve Replacement, or Repair: PAPABEAR: a randomized controlled trial

Context  Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. Objective  To determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. Design, Setting, and Patients  Double-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft (CABG) surgery and/or valve replacement/repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year. Intervention  Oral amiodarone (10 mg/kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery (13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative -blockers. Main Outcome Measure  Incidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day. Results  Atrial tachyarrhythmias occurred in fewer amiodarone patients (48/299; 16.1%) than in placebo patients (89/302; 29.5%) overall (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34-0.69; P<.001); in patients younger than 65 years (19 [11.2%] vs 36 [21.1%]; HR, 0.51 [95% CI, 0.28-0.94]; P = .02); in patients aged 65 years or older (28 [21.7%] vs 54 [41.2%]; HR, 0.45 [95% CI, 0.27-0.75]; P<.001); in patients who had CABG surgery only (22 [11.3%] vs 46 [23.6%]; HR, 0.45 [95% CI, 0.26-0.79]; P = .002); in patients who had valve replacement/repair surgery with or without CABG surgery (25 [23.8%] vs 44 [44.1%]; HR, 0.51 [95% CI, 0.31-0.84; P = .008); in patients who received preoperative -blocker therapy (27 [15.3%] vs 42 [25.0%]; HR, 0.58 [95% CI, 0.34-0.99]; P = .03); and in patients who did not receive preoperative -blocker therapy (20 [16.3%] vs 48 [35.8%]; HR, 0.40 [95% CI, 0.22-0.71]; P<.001), respectively. Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients (1/299; 0.3%) than in placebo patients (8/302; 2.6%) (P = .04). Dosage reductions of blinded therapy were more common in amiodarone patients (34/299; 11.4%) than in placebo patients (16/302; 5.3%) (P = .008). There were no differences in serious postoperative complications, in-hospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality. Conclusion  Oral amiodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and may be safe overall and in important patient subgroups. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00251706      

Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial

Context  Glucose-insulin-potassium (GIK) infusion is a widely applicable, low-cost therapy that has been postulated to improve mortality in patients with acute ST-segment elevation myocardial infarction (STEMI). Given the potential global importance of GIK infusion, a large, adequately powered randomized trial is required to determine the effect of GIK on mortality in patients with STEMI. Objective  To determine the effect of high-dose GIK infusion on mortality in patients with STEMI. Design, Setting, and Participants  Randomized controlled trial conducted in 470 centers worldwide among 20 201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used. Intervention  Patients were randomly assigned to receive GIK intravenous infusion for 24 hours plus usual care (n = 10 091) or to receive usual care alone (controls; n = 10 110). Main Outcome Measures  Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization. Results  At 30 days, 976 control patients (9.7%) and 1004 GIK infusion patients (10.0%) died (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.95-1.13; P = .45). There were no significant differences in the rates of cardiac arrest (1.5% [151/10 107] in control and 1.4% [139/10 088] in GIK infusion; HR, 0.93; 95% CI, 0.74-1.17; P = .51), cardiogenic shock (6.3% [640/10 107] vs 6.6% [667/10 088]; HR, 1.05; 95% CI, 0.94-1.17; P = .38), or reinfarction (2.4% [246/10 107] vs 2.3% [236/10 088]; HR, 0.98; 95% CI, 0.82-1.17; P = .81). The rates of heart failure at 7 days after randomization were also similar between the groups (16.9% [1711/10 107] vs 17.1% [1721/10 088]; HR, 1.01; 95% CI, 0.95-1.08; P = .72). The lack of benefit of GIK infusion on mortality was consistent in prespecified subgroups, including in those with and without diabetes, in those presenting with and without heart failure, in those presenting early and later after symptom onset, and in those receiving and not receiving reperfusion therapy (thrombolysis or primary percutaneous coronary intervention). Conclusion  In this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI.      

Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial

Context  Ranolazine is a novel antianginal agent that reduces ischemia in patients with chronic angina but has not been studied in patients with acute coronary syndromes (ACS). Objective  To determine the efficacy and safety of ranolazine during long-term treatment of patients with non–ST-elevation ACS. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled, multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, n = 3279) or matching placebo (n = 3281), and followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial between October 8, 2004, and February 14, 2007. Main Outcome Measures  The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end of study. The major safety end points were death from any cause and symptomatic documented arrhythmia. Results  The primary end point occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P = .11). The major secondary end point (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86-1.08; P = .50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P = .87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P = .03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P = .84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80-1.22; P = .91). Conclusions  The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy. Trial Registration  clinicaltrials.gov Identifier: NCT00099788      

Chronic conditions, functional limitations, and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s

Context  Information on the school-age functioning and special health care needs of extremely low-birth-weight (ELBW, <1000 g) children is necessary to plan for medical and educational services. Objective  To examine neurosensory, developmental, and medical conditions together with the associated functional limitations and special health care needs of ELBW children compared with normal-birth-weight (NBW) term-born children (controls). Design, Setting, and Participants  A follow-up study at age 8 years of a cohort of 219 ELBW children born 1992 to 1995 (92% of survivors) and 176 NBW controls of similar sociodemographic status conducted in Cleveland, Ohio. Main Outcome Measures  Parent Questionnaire for Identifying Children with Chronic Conditions of 12 months or more and categorization of specific medical diagnoses and developmental disabilities based on examination of the children. Results  In logistic regression analyses adjusting for sociodemographic status and sex, ELBW children had significantly more chronic conditions than NBW controls, including functional limitations (64% vs 20%, respectively; odds ratio [OR], 8.1; 95% confidence interval [CI], 5.0-13.1; P<.001), compensatory dependency needs (48% vs 23%, respectively; OR, 3.0; 95% CI, 1.9-4.7; P<.001), and services above those routinely required by children (65% vs 27%, respectively; OR, 5.4; 95% CI, 3.4-8.5; P<.001). These differences remained significant when the 36 ELBW children with neurosensory impairments were excluded. Specific diagnoses and disabilities for ELBW vs NBW children included cerebral palsy (14% vs 0%, respectively; P<.001), asthma (21% vs 9%; OR, 3.0; 95% CI, 1.6-5.6; P = .001), vision of less than 20/200 (10% vs 3%; OR, 3.1; 95% CI, 1.2-7.8; P = .02), low IQ of less than 85 (38% vs 14%; OR, 4.5; 95% CI, 2.7-7.7; P<.001), limited academic skills (37% vs 15%; OR, 4.2; 95% CI, 2.5-7.3; P<.001), poor motor skills (47% vs 10%; OR, 7.8; 95% CI, 4.5-13.6; P<.001), and poor adaptive functioning (69% vs 34%; OR, 6.5; 95% CI, 4.0-10.6; P<.001). Conclusion  The ELBW survivors in school at age 8 years who were born in the 1990s have considerable long-term health and educational needs.      

Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial

Context  The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. Objective  To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD. Design, Setting, and Participants  Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured atherosclerosis progression by intravascular ultrasound (IVUS). Interventions  Patients were randomized to receive amlodipine, 10 mg; enalapril, 20 mg; or placebo. IVUS was performed at baseline and study completion. Main Outcome Measures  The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo. Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, hospitalization for angina pectoris, hospitalization for congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS end point was change in percent atheroma volume. Results  Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients (hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]), and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07 [P = .16]. Primary end point comparison for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04 [P = .10]). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo (P = .12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = .02). Compared with baseline, IVUS showed progression in the placebo group (P<.001), a trend toward progression in the enalapril group (P = .08), and no progression in the amlodipine group (P = .31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19, P = .07. Conclusions  Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.      

Prognostic significance of left ventricular mass change during treatment of hypertension

Context  Increased baseline left ventricular (LV) mass predicts cardiovascular (CV) complications of hypertension, but the relation between lower LV mass and outcome during treatment for hypertension is uncertain. Objective  To determine whether reduction of LV mass during antihypertensive treatment modifies risk of major CV events independent of blood pressure change. Design, Setting, and Participants  Prospective cohort substudy of the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) randomized clinical trial, conducted from 1995 to 2001. A total of 941 prospectively identified patients aged 55 to 80 years with essential hypertension and electrocardiographic LV hypertrophy had LV mass measured by echocardiography at enrollment in the LIFE trial and thereafter were followed up annually for a mean (SD) of 4.8 (1.0) years for CV events. Main Outcome Measures  Composite end point of CV death, fatal or nonfatal myocardial infarction, and fatal or nonfatal stroke. Results  The composite end point occurred in 104 patients (11%). The multivariable Cox regression model showed a strong association between lower in-treatment LV mass index and reduced rate of the composite CV end point (hazard ratio [HR], 0.78 per 1-SD (25.3) decrease in LV mass index; 95% confidence interval [CI], 0.65-0.94; P = .009) over and above that predicted by reduction in blood pressure. There were parallel associations between lower in-treatment LV mass index and lower CV mortality (HR, 0.62; 95% CI, 0.47-0.82; P = .001), stroke (HR, 0.76; 95% CI, 0.60-0.96; P = .02), myocardial infarction (HR, 0.85; 95% CI, 0.62-1.17, P = .33), and all-cause mortality (HR, 0.72; 95% CI, 0.59-0.88, P = .002), independent of systolic blood pressure and assigned treatment. Results were confirmed in analyses adjusting for additional CV risk factors, electrocardiographic changes, or when only considering events after the first year of study treatment. Conclusion  In patients with essential hypertension and baseline electrocardiographic LV hypertrophy, lower LV mass during antihypertensive treatment is associated with lower rates of clinical end points, additional to effects of blood pressure lowering and treatment modality.      

Outcomes and complications associated with off-label and untested use of drug-eluting stents

Context  Limited data exist regarding use of drug-eluting stents outside of approved indications in real-world settings. Objectives  To determine the frequency, safety, and effectiveness of drug-eluting stents for off-label (restenosis, bypass graft lesion, long lesions, vessel size outside of information for use recommendation) and untested (left main, ostial, bifurcation, or total occlusion lesions) indications in percutaneous coronary intervention (PCI). Design, Setting, and Patients  Observational, prospective, multicenter registry to evaluate in-hospital, 30-day, and 1-year outcomes among patients undergoing PCI between January and June 2005 in 140 US academic and community medical centers. Of 7752 PCI-treated patients, 6993 (90%) received drug-eluting stents; of these, 5851 (84%) received no other devices. Standard, off-label, and untested use was determined in 5541 (95%) of these 5851 patients, constituting the study cohort. Main Outcome Measures  Frequency of off-label and untested use, 1-year repeat target vessel revascularization, and composite of death, myocardial infarction (MI), or stent thrombosis at in-hospital follow-up and during 1 year of follow-up. Results  Of 5541 patients receiving drug-eluting stents, 2588 (47%) received stents for off-label or untested indications. Adjusted in-hospital risk of death, MI, or stent thrombosis was not statistically different with off-label or untested vs standard use. At 30 days, the risk of this composite end point was significantly higher with off-label use (adjusted hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.24-3.48; P = .005) but not untested use (adjusted HR, 1.45; 95% CI, 0.79-2.67; P = .23). Excluding early events, this end point was not different at 1 year with off-label use (adjusted HR, 1.10; 95% CI, 0.79-1.54; P = .57) or untested use (adjusted HR, 0.91; 95% CI, 0.60-1.38; P = .66). At 1 year, compared with standard use, significantly higher rates of target vessel revascularization were associated with off-label use (adjusted HR, 1.49; 95% CI, 1.13-1.98; P = .005) and untested use (adjusted HR, 1.49; 95% CI, 1.10-2.02; P = .01), although absolute rates were low (standard, 4.4% [n = 113]; off-label, 7.6% [n = 95]; untested, 6.7% [n = 72]). Conclusions  In contemporary US practice, off-label and untested use of drug-eluting stents is common. Compared with standard use, relative early safety is lower with off-label use, and the long-term effectiveness is lower with both off-label and untested use. However, the absolute event rates remain low.      

High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial

Context  The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days. Objective  To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up. Design, Setting, and Patients  Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year. Main Outcome Measures  Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator–reported need for rehospitalization; 1-year outcome was all-cause death. Results  Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55). Conclusions  In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies. ClinicalTrials.gov Identifier:  NCT00043784.      

Medicine residents' understanding of the biostatistics and results in the medical literature

Context  Physicians depend on the medical literature to keep current with clinical information. Little is known about residents' ability to understand statistical methods or how to appropriately interpret research outcomes. Objective  To evaluate residents' understanding of biostatistics and interpretation of research results. Design, Setting, and Participants  Multiprogram cross-sectional survey of internal medicine residents. Main Outcome Measure  Percentage of questions correct on a biostatistics/study design multiple-choice knowledge test. Results  The survey was completed by 277 of 367 residents (75.5%) in 11 residency programs. The overall mean percentage correct on statistical knowledge and interpretation of results was 41.4% (95% confidence interval [CI], 39.7%-43.3%) vs 71.5% (95% CI, 57.5%-85.5%) for fellows and general medicine faculty with research training (P < .001). Higher scores in residents were associated with additional advanced degrees (50.0% [95% CI, 44.5%-55.5%] vs 40.1% [95% CI, 38.3%-42.0%]; P < .001); prior biostatistics training (45.2% [95% CI, 42.7%-47.8%] vs 37.9% [95% CI, 35.4%-40.3%]; P = .001); enrollment in a university-based training program (43.0% [95% CI, 41.0%-45.1%] vs 36.3% [95% CI, 32.6%-40.0%]; P = .002); and male sex (44.0% [95% CI, 41.4%-46.7%] vs 38.8% [95% CI, 36.4%-41.1%]; P = .004). On individual knowledge questions, 81.6% correctly interpreted a relative risk. Residents were less likely to know how to interpret an adjusted odds ratio from a multivariate regression analysis (37.4%) or the results of a Kaplan-Meier analysis (10.5%). Seventy-five percent indicated they did not understand all of the statistics they encountered in journal articles, but 95% felt it was important to understand these concepts to be an intelligent reader of the literature. Conclusions  Most residents in this study lacked the knowledge in biostatistics needed to interpret many of the results in published clinical research. Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.      

Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis

Context  In patients with acute cardiogenic pulmonary edema noninvasive ventilation may reduce intubation rate, but the impact on mortality and the superiority of one technique over another have not been clearly established. Objective  To systematically review and quantitatively synthesize the short-term effect of noninvasive ventilation on major clinical outcomes. Data Sources  MEDLINE and EMBASE (from inception to October 2005) and Cochrane databases (library issue 4, 2005) were searched to identify relevant randomized controlled trials and systematic reviews published from January 1, 1988, to October 31, 2005. Study Selection and Data Extraction  Included trials were all parallel studies comparing noninvasive ventilation to conventional oxygen therapy in patients with acute pulmonary edema. Comparisons of different techniques, either continuous positive airway pressure (CPAP) or bilevel noninvasive pressure support ventilation (NIPSV), were also included. Data Synthesis  Fifteen trials were selected. Overall, noninvasive ventilation significantly reduced the mortality rate by nearly 45% compared with conventional therapy (risk ratio [RR], 0.55; 95% confidence interval [CI], 0.40-0.78; P = .72 for heterogeneity). The results were significant for CPAP (RR, 0.53; 95% CI, 0.35-0.81; P = .44 for heterogeneity) but not for NIPSV (RR, 0.60; 95% CI, 0.34-1.05; P = .76 for heterogeneity), although there were fewer studies in the latter. Both modalities showed a significant decrease in the "need to intubate" rate compared with conventional therapy: CPAP (RR, 0.40; 95% CI, 0.27-0.58; P = .21 for heterogeneity), NIPSV (RR, 0.48; 95% CI, 0.30-0.76; P = .24 for heterogeneity), and together (RR, 0.43; 95% CI, 0.32-0.57; P = .20 for heterogeneity). There were no differences in intubation or mortality rates in the analysis of studies comparing the 2 techniques. Conclusions  Noninvasive ventilation reduces the need for intubation and mortality in patients with acute cardiogenic pulmonary edema. Although the level of evidence is higher for CPAP, there are no significant differences in clinical outcomes when comparing CPAP vs NIPSV.      

Obesity, weight gain, and the risk of kidney stones

Context  Larger body size may result in increased urinary excretion of calcium, oxalate, and uric acid, thereby increasing the risk for calcium-containing kidney stones. It is unclear if obesity increases the risk of stone formation, and it is not known if weight gain influences risk. Objective  To determine if weight, weight gain, body mass index (BMI), and waist circumference are associated with kidney stone formation. Design, Setting, and Participants  A prospective study of 3 large cohorts: the Health Professionals Follow-up Study (N = 45 988 men; age range at baseline, 40-75 years), the Nurses’ Health Study I (N = 93 758 older women; age range at baseline, 34-59 years), and the Nurses’ Health Study II (N = 101 877 younger women; age range at baseline, 27-44 years). Main Outcome Measures  Incidence of symptomatic kidney stones. Results  We documented 4827 incident kidney stones over a combined 46 years of follow-up. After adjusting for age, dietary factors, fluid intake, and thiazide use, the relative risk (RR) for stone formation in men weighing more than 220 lb (100.0 kg) vs men less than 150 lb (68.2 kg) was 1.44 (95% confidence interval [CI], 1.11-1.86; P = .002 for trend). In older and younger women, RRs for these weight categories were 1.89 (95% CI, 1.52-2.36; P<.001 for trend) and 1.92 (95% CI, 1.59-2.31; P<.001 for trend), respectively. The RR in men who gained more than 35 lb (15.9 kg) since age 21 years vs men whose weight did not change was 1.39 (95% CI, 1.14-1.70; P = .001 for trend). Corresponding RRs for the same categories of weight gain since age 18 years in older and younger women were 1.70 (95% CI, 1.40-2.05; P<.001 for trend) and 1.82 (95% CI, 1.50-2.21; P<.001 for trend). Body mass index was associated with the risk of kidney stone formation: the RR for men with a BMI of 30 or greater vs those with a BMI of 21 to 22.9 was 1.33 (95% CI, 1.08-1.63; P<.001 for trend). Corresponding RRs for the same categories of BMI in older and younger women were 1.90 (95% CI, 1.61-2.25; P<.001 for trend) and 2.09 (95% CI, 1.77-2.48; P<.001 for trend). Waist circumference was also positively associated with risk in men (P = .002 for trend) and in older and younger women (P<.001 for trend for both). Conclusions  Obesity and weight gain increase the risk of kidney stone formation. The magnitude of the increased risk may be greater in women than in men.      

Differences in mortality and use of revascularization in black and white patients with acute MI admitted to hospitals with and without revascularization services

Context  Racial differences in the use of coronary revascularization after acute myocardial infarction (AMI) have been widely reported. However, few studies have examined patterns of care for AMI patients admitted to hospitals with and without revascularization services. Objective  To compare rates of hospital transfer, coronary revascularization, and mortality after AMI for black and white patients admitted to hospitals with and without revascularization services. Design, Setting, and Participants  Retrospective cohort study of 1 215 924 black and white Medicare beneficiaries aged 68 years and older, admitted with AMI between January 1, 2000, and June 30, 2005, to 4627 US hospitals with and without revascularization services. Main Outcome Measures  For patients admitted to nonrevascularization hospitals, transfer to another hospital with revascularization services; for all patients, risk-adjusted rates of 30-day coronary revascularization and 1-year mortality. Results  Black patients admitted to hospitals without revascularization were less likely (25.2% vs 31.0%; P<.001) to be transferred. Black patients admitted to hospitals with or without revascularization services were less likely to undergo revascularization than white patients (34.3% vs 50.2% and 18.3% vs 25.9%; P<.001) and had higher 1-year mortality (35.3% vs 30.2% and 39.7% vs 37.6%; P<.001). After adjustment for sociodemographics, comorbidity, and illness severity, blacks remained less likely to be transferred (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.75-0.81; P<.001) and undergo revascularization (HR, 0.71; 95% CI, 0.69-0.74; P<.001; and HR, 0.68; 95% CI, 0.65-0.70; P<.001 in hospitals with and without revascularization, respectively). Risk-adjusted mortality was lower for blacks during the first 30 days after admission (HR, 0.91; 95% CI, 0.88-0.93; P<.001; and HR, 0.90; 95% CI, 0.87-0.92; P<.001 in hospitals with and without revascularization, respectively) but was higher (P<.001) thereafter. Conclusions  Black patients admitted to hospitals with and without coronary revascularization services are less likely to receive coronary revascularization. The higher long-term mortality of black patients may reflect the lower use of revascularization or other aspects of AMI care.      

Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials

Context  Patients with unstable angina or non–ST-segment elevation myocardial infarction (NSTEMI) can be cared for with a routine invasive strategy involving coronary angiography and revascularization or more conservatively with a selective invasive strategy in which only those with recurrent or inducible ischemia are referred for acute intervention. Objective  To conduct a meta-analysis that compares benefits and risks of routine invasive vs selective invasive strategies. Data Sources  Randomized controlled trials identified through search of MEDLINE and the Cochrane databases (1970 through June 2004) and hand searching of cross-references from original articles and reviews. Study Selection  Trials were included that involved patients with unstable angina or NSTEMI who received a routine invasive or a selective invasive strategy. Data Extraction  Major outcomes of death and myocardial infarction (MI) occurring from initial hospitalization to the end of follow-up were extracted from published results of eligible trials. Data Synthesis  A total of 7 trials (N = 9212 patients) were eligible. Overall, death or MI was reduced from 663 (14.4%) of 4604 patients in the selective invasive group to 561 (12.2%) of 4608 patients in the routine invasive group (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.72-0.93; P = .001). There was a nonsignificant trend toward fewer deaths (6.0% vs 5.5%; OR, 0.92; 95% CI, 0.77-1.09; P = .33) and a significant reduction in MI alone (9.4% vs 7.3%; OR, 0.75; 95% CI, 0.65-0.88; P<.001). Higher-risk patients with elevated cardiac biomarker levels at baseline benefited more from routine intervention, with no significant benefit observed in lower-risk patients with negative baseline marker levels. During the initial hospitalization, a routine invasive strategy was associated with a significantly higher early mortality (1.1% vs 1.8% for selective vs routine, respectively; OR, 1.60; 95% CI, 1.14-2.25; P = .007) and the composite of death or MI (3.8% vs 5.2%; OR, 1.36; 95% CI, 1.12-1.66; P = .002). But after discharge, the routine invasive strategy was associated with fewer subsequent deaths (4.9% vs 3.8%; OR, 0.76; 95% CI, 0.62-0.94; P = .01) and the composite of death or MI (11.0% vs 7.4%; OR, 0.64; 95% CI, 0.56-0.75; P<.001). At the end of follow-up, there was a 33% reduction in severe angina (14.0% vs 11.2%; OR, 0.77; 95% CI, 0.68-0.87; P<.001) and a 34% reduction in rehospitalization (41.3% vs 32.5%; OR, 0.66; 95% CI, 0.60-0.72; P<.001) with a routine invasive strategy. Conclusions  A routine invasive strategy exceeded a selective invasive strategy in reducing MI, severe angina, and rehospitalization over a mean follow-up of 17 months. But routine intervention was associated with a higher early mortality hazard and a trend toward a mortality reduction at follow-up. Future strategies should explore ways to minimize the early hazard and enhance later benefits by focusing on higher-risk patients and optimizing timing of intervention and use of proven therapies.      

High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial

Context  Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease. Objective  To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI). Design, Setting, and Participants  The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI. Interventions  Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n = 4439), or usual-dose simvastatin (20 mg/d; n = 4449). Main Outcome Measure  Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. Results  During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71-0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76-0.91; P<.001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73-1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P<.001). Serious myopathy and rhabdomyolysis were rare in both groups. Conclusions  In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions. Trial Registration  ClinicalTrials.gov Identifier: NCT00159835.      

Effects of antibiotic therapy on outcomes of patients with coronary artery disease: a meta-analysis of randomized controlled trials

Context  Although Chlamydia pneumoniae infection has been associated with the initiation and progression of atherosclerosis, results of clinical trials investigating antichlamydial antibiotics as adjuncts to standard therapy in patients with coronary artery disease (CAD) have been inconsistent. Objective  To conduct a meta-analysis of clinical trials of antichlamydial antibiotic therapy in patients with CAD. Data Sources  The MEDLINE and Cochrane Central Register of Controlled Trials databases were searched from 1966 to April 2005 for English-language trials of antibiotic therapy in patients with CAD. Bibliographies of retrieved articles were searched for further studies. Presentations at major scientific meetings (2003-2004) were also reviewed. Search terms included antibacterial agents, myocardial infarction, unstable angina, and coronary arteriosclerosis. Study Selection  Eligible studies were prospective, randomized, placebo-controlled trials of antichlamydial antibiotic therapy in patients with CAD that reported all-cause mortality, myocardial infarction, or unstable angina. Of the 110 potentially relevant articles identified, 11 reports enrolling 19 217 patients were included. Data Extraction  Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, and end points. End points of interest included all-cause mortality, myocardial infarction (MI), and a combined end point of MI and unstable angina. Data Synthesis  Event rates were combined using a random-effects model. Antibiotic therapy had no impact on all-cause mortality among treated vs untreated patients (4.7% vs 4.6%; odds ratio [OR], 1.02; 95% confidence interval [CI], 0.89-1.16; P = .83), on the rates of MI (5.0% vs 5.4%; OR, 0.92; 95% CI, 0.81-1.04; P = .19), or on the combined end point of MI and unstable angina (9.2% vs 9.6%; OR, 0.91; 95% CI, 0.76-1.07; P = .25). Conclusion  Evidence available to date does not demonstrate an overall benefit of antibiotic therapy in reducing mortality or cardiovascular events in patients with CAD.      

Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial

Context  Comorbidities may increase the negative effects of specific anticancer treatments such as androgen suppression therapy (AST). Objectives  To compare 6 months of AST and radiation therapy (RT) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality. Design, Setting, and Patients  At academic and community-based medical centers in Massachusetts, between December 1, 1995, and April 15, 2001, 206 men with localized but unfavorable-risk prostate cancer were randomized to receive RT alone or RT and AST combined. All-cause mortality estimates stratified by randomized treatment group and further stratified in a postrandomization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test. Main Outcome Measure  Time to all-cause mortality. Results  As of January 15, 2007, with a median follow-up of 7.6 (range, 0.5-11.0) years, 74 deaths have occurred. A significant increase in the risk of all-cause mortality (44 vs 30 deaths; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1-2.9; P = .01) was observed in men randomized to RT compared with RT and AST. However, the increased risk in all-cause mortality appeared to apply only to men randomized to RT with no or minimal comorbidity (31 vs 11 deaths; HR, 4.2; 95% CI, 2.1-8.5; P < .001). Among men with moderate or severe comorbidity, those randomized to RT alone vs RT and AST did not have an increased risk of all-cause mortality (13 vs 19 deaths; HR, 0.54; 95% CI, 0.27-1.10; P = .08). Conclusions  The addition of 6 months of AST to RT resulted in increased overall survival in men with localized but unfavorable-risk prostate cancer. This result may pertain only to men without moderate or severe comorbidity, but this requires further assessment in a clinical trial specifically designed to assess this interaction. Trial Registration  clinicaltrials.gov Identifier: NCT00116220      

Glucose-insulin-potassium therapy in patients with ST-segment elevation myocardial infarction

Context  The clinical benefit of glucose-insulin-potassium (GIK) infusion in patients with ST-segment elevation myocardial infarction (STEMI) is unclear. While some smaller trials suggest benefit, in the CREATE-ECLA trial, GIK infusion had no effect on 30-day mortality in 20 201 patients. Objectives  To determine the association between GIK infusion therapy and 30-day and 6-month outcomes in patients with STEMI. Design, Setting, and Participants  Primary analysis of the OASIS-6 GIK randomized controlled trial of 2748 patients with acute STEMI; prespecified analyses of the combined trial data from the OASIS-6 GIK and CREATE-ECLA GIK trial populations of 22 943 patients with acute STEMI; subgroup analysis on the timing of initiation of GIK infusion therapy and outcomes; and post hoc analyses exploring whether GIK infusion may cause early harm by increasing glucose and potassium levels and net fluid gain. Intervention  High-dose GIK solution consisting of 25% glucose, 50 U/L of regular insulin, and 80 mEq/L of potassium infused at 1.5 mL/kg per hour for 24 hours. Main Outcome Measures  Mortality rates at 30 days and 6 months in the OASIS-6 GIK trial and rates of death, heart failure, and the composite of death or heart failure at 3 and 30 days in the combined OASIS-6 GIK and CREATE-ECLA GIK trial populations. Results  At 6 months, 148 (10.8%) GIK infusion patients and 143 (10.4%) control patients died in the OASIS-6 trial (hazard ratio [HR], 1.04; 95% CI, 0.83-1.31; P = .72); 153 (11.1%) GIK patients and 185 (13.5%) control patients had heart failure (HR, 0.83; 95% CI, 0.67-1.02; P = .08); and 240 (17.5%) GIK patients and 264 (19.2%) control patients had a composite of death or heart failure (HR, 0.91; 95% CI, 0.76-1.08; P = .27). In the prespecified analyses of the combined trial data, there were 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group at 3 days (HR, 1.13; 95% CI, 1.02-1.26; P = .03). This difference disappeared by 30 days, with 1108 deaths (9.7%) in the GIK group and 1068 (9.3%) in the control group (HR, 1.04; 95% CI, 0.96-1.13; P = .33). GIK therapy increased levels of glucose, potassium, and net fluid gain postinfusion, all 3 of which predicted death after adjusting for multiple confounders. Adjusting for glucose, potassium, and net fluid gain eliminated the apparent increase in mortality at 3 days observed with GIK infusion, suggesting a direct association with these factors. Administration of GIK infusion within 4 hours of symptom onset yielded no benefit compared with later initiation. Conclusions  Infusion of GIK provided no benefit and may cause early harm following STEMI. Avoidance of infusion-related hyperglycemia, hyperkalemia, and net fluid gain may be advisable in future studies of metabolic modulation in patients with STEMI. Trial Registration  clinicaltrials.gov Identifier: NCT00064428      

Prognostic value of placental growth factor in patients with acute chest pain

Context  Experimental data suggest that placental growth factor (PlGF), a member of the vascular endothelial growth factor family, acts as a primary inflammatory instigator of atherosclerotic plaque instability and thus may be useful as a risk-predicting biomarker in patients with acute coronary syndromes (ACS). Objective  To determine whether blood levels of PlGF predict risk for death or nonfatal myocardial infarction in patients with acute chest pain. Design, Setting, and Patients  Measurement of PlGF levels as well as levels of markers of myocardial necrosis (troponin T [TnT]), platelet activation (soluble CD40 ligand [sCD40L]), and inflammation (high-sensitivity C-reactive protein [hsCRP]) in an inception cohort of 547 patients with angiographically validated ACS participating in the CAPTURE (c7E3 Fab Anti-Platelet Therapy in Unstable Refractory Angina) trial and in a heterogeneous cohort of 626 patients presenting with acute chest pain to an emergency department in Germany between December 1996 and March 1999. Main Outcome Measure  Risk for death or nonfatal myocardial infarction after 30 days. Results  In patients with ACS, elevated PlGF levels (>27.0 ng/L; 40.8% of patients) indicated a markedly increased risk of events at 30 days (14.8% vs 4.9%; unadjusted hazard ratio [HR], 3.34; 95% confidence interval [CI], 1.79-6.24; P<.001). In a multivariable model, elevated levels of TnT (HR, 1.83; 95% CI, 1.05-3.86; P = .03), sCD40L (HR, 2.65; 95% CI, 1.41-4.99; P = .002), and PlGF (HR, 3.03; 95% CI, 1.54-5.95; P<.001) were independent predictors, while elevated hsCRP level was not (HR, 0.98; 95% CI, 0.53-1.98; P = .94). In patients with acute chest pain, elevated levels of PlGF predicted risk (21.2% vs 5.3%) (unadjusted: HR, 4.80; 95% CI, 2.81-8.21; P<.001; adjusted: HR, 3.00; 95% CI, 1.68-5.38; P<.001). Patients negative for all 3 markers (TnT, sCD40L, and PlGF) were at very low cardiac risk (7 days: no event; 30 days: 2.1% event rate). Conclusions  Plasma PlGF levels may be an independent biomarker of adverse outcome in patients with suspected ACS. A single initial measurement of plasma PlGF appears to extend the predictive and prognostic information gained from traditional inflammatory markers.      

Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials

Context  The benefits of abciximab in patients with ST-segment elevation myocardial infarction (STEMI) are still a matter of debate. Objective  To combine data from all randomized trials conducted with abciximab in STEMI. Data Sources  Formal searches of electronic databases (MEDLINE, PubMed) from from January 1990 to December 2004. Study Selection  We examined all completed, published, randomized trials of abciximab in STEMI. The following key words were used for study selection: randomized trial, myocardial infarction, reperfusion, primary angioplasty, facilitated angioplasty, stenting, fibrinolysis, IIb-IIIa inhibitors, and abciximab. Data Extraction  Information on study design, type and dosage of drugs, inclusion and exclusion criteria, number of patients, and clinical outcome was extracted by 2 investigators. Disagreements were resolved by consensus. Data Synthesis  Eleven trials were analyzed, involving 27115 patients (12 602 [46.5%] in the abciximab group, 14 513 [53.5%] in the control group). When compared with the control group, abciximab was associated with a significant reduction in short-term (30 days) mortality (2.4% vs 3.4%, P = .047) and long-term (6-12 months) mortality (4.4% vs 6.2%, P = .01) in patients undergoing primary angioplasty but not in those treated with fibrinolysis or in all trials combined. Abciximab was associated with a significant reduction in 30-day reinfarction, both in all trials combined (2.1% vs 3.3%, P<.001), in primary angioplasty (1.0% vs 1.9%, P = .03), and in fibrinolysis trials (2.3% vs 3.6%, P<.001). Abciximab did not result in an increased risk of intracranial bleeding (0.61% vs 0.62%, P = .62) but was associated with an increased risk of major bleeding complications when combined with fibrinolysis (5.2% vs 3.1%, P<.001) but not with primary angioplasty (4.7% vs 4.1%, P = .36). Conclusions  This meta-analysis shows that, when compared with the control group, adjunctive abciximab for STEMI is associated with a significant reduction in 30-day and long-term mortality in patients treated with primary angioplasty but not in those receiving fibrinolysis. The 30-day reinfarction rate is significantly reduced in patients treated with either fibrinolysis or primary angioplasty. A higher risk of major bleeding complications is observed with abciximab in association with fibrinolysis.