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      

Contemporary clinical profile and outcome of prosthetic valve endocarditis

Context  Prosthetic valve endocarditis (PVE) is associated with significant mortality and morbidity. The contemporary clinical profile and outcome of PVE are not well defined. Objectives  To describe the prevalence, clinical characteristics, and outcome of PVE, with attention to health care–associated infection, and to determine prognostic factors associated with in-hospital mortality. Design, Setting, and Participants  Prospective, observational cohort study conducted at 61 medical centers in 28 countries, including 556 patients with definite PVE as defined by Duke University diagnostic criteria who were enrolled in the International Collaboration on Endocarditis-Prospective Cohort Study from June 2000 to August 2005. Main Outcome Measure  In-hospital mortality. Results  Definite PVE was present in 556 (20.1%) of 2670 patients with infective endocarditis. Staphylococcus aureus was the most common causative organism (128 patients [23.0%]), followed by coagulase-negative staphylococci (94 patients [16.9%]). Health care–associated PVE was present in 203 (36.5%) of the overall cohort. Seventy-one percent of health care–associated PVE occurred within the first year of valve implantation, and the majority of cases were diagnosed after the early (60-day) period. Surgery was performed in 272 (48.9%) patients during the index hospitalization. In-hospital death occurred in 127 (22.8%) patients and was predicted by older age, health care–associated infection (62/203 [30.5%]; adjusted odds ratio [OR], 1.62; 95% confidence interval [CI], 1.08-2.44; P = .02), S aureus infection (44/128 [34.4%]; adjusted OR, 1.73; 95% CI, 1.01-2.95; P = .05), and complications of PVE, including heart failure (60/183 [32.8%]; adjusted OR, 2.33; 95% CI, 1.62-3.34; P<.001), stroke (34/101 [33.7%]; adjusted OR, 2.25; 95% CI, 1.25-4.03; P = .007), intracardiac abscess (47/144 [32.6%]; adjusted OR, 1.86; 95% CI, 1.10-3.15; P = .02), and persistent bacteremia (27/49 [55.1%]; adjusted OR, 4.29; 95% CI, 1.99-9.22; P<.001). Conclusions  Prosthetic valve endocarditis accounts for a high percentage of all cases of infective endocarditis in many regions of the world. Staphylococcus aureus is now the leading cause of PVE. Health care–associated infection significantly influences the clinical characteristics and outcome of PVE. Complications of PVE strongly predict in-hospital mortality, which remains high despite prompt diagnosis and the frequent use of surgical intervention.      

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.      

Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation

Context  Although reperfusion therapy, aspirin, -blockers, and angiotensin-converting enzyme inhibitors reduce mortality when used early in patients with acute myocardial infarction (MI), mortality and morbidity remain high. No antithrombotic or newer antiplatelet drug has been shown to reduce mortality in acute MI. Objective  To evaluate the effects of reviparin, a low-molecular-weight heparin, when initiated early and given for 7 days in addition to usual therapy on the primary composite outcome of death, myocardial reinfarction, or strokes at 7 and 30 days. Design, Setting, and Patients  A randomized, double-blind, placebo-controlled trial (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]) of 15 570 patients with ST-segment elevation or new left bundle-branch block, presenting within 12 hours of symptom onset at 341 hospitals in India and China from July 2001 through July 2004. Intervention  Reviparin or placebo subcutaneously twice daily for 7 days. Main Outcome Measure  Primary composite outcome of death, myocardial reinfarction, or stroke at 7 and 30 days. Results  The primary composite outcome was significantly reduced from 854 (11.0%) of 7790 patients in the placebo group to 745 (9.6%) of 7780 in the reviparin group (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96; P = .005). These benefits persisted at 30 days (1056 [13.6%] vs 921 [11.8%] patients; HR, 0.87; 95% CI, 0.79-0.95; P = .001) with significant reductions in 30-day mortality (877 [11.3%] vs 766 [9.8%]; HR, 0.87; 95% CI, 0.79-0.96; P = .005) and reinfarction (199 [2.6%] vs 154 [2.0%]; HR, 0.77; 95% CI, 0.62-0.95; P = .01), and no significant differences in strokes (64 [0.8%] vs 80 [1.0%]; P = .19). Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52-0.96; P = .03; 30/1000 events prevented; 2 to <4 hours: HR, 0.81; 95% CI, 0.67-0.98; P = .03; 21/1000 events prevented; 4 to <8 hours: HR, 0.85; 95% CI, 0.73-0.99; P = .05; 16/1000 events prevented; and 8 hours: HR, 1.06; 95% CI, 0.86-1.30; P = .58; P = .04 for trend). There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2%] vs 7 [0.1%], respectively; P = .07), but the absolute excess was small (1 more per 1000) vs reductions in the primary outcome (18 fewer per 1000) or mortality (15 fewer per 1000). Conclusions  In patients with acute ST-segment elevation or new left bundle-branch block MI, reviparin reduces mortality and reinfarction, without a substantive increase in overall stroke rates. There is a small absolute excess of life-threatening bleeding but the benefits outweigh the risks.      

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.      

Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease

Context  Elevated concentrations of B-type natriuretic peptide (BNP) at presentation in patients with acute coronary syndrome (ACS) are associated with long-term mortality. Few data exist regarding serial assessment of BNP levels during follow-up. Objective  To determine whether concentrations of BNP at study entry (prior to hospital discharge for ACS) and at outpatient follow-up at 4 months and 12 months are associated with subsequent clinical outcomes. Design, Setting, and Patients  Prospective observational substudy of 4497 patients with non–ST-elevation or ST-elevation ACS who were enrolled in phase Z of the A to Z trial, which was conducted in 41 countries at 322 acute care hospitals between 1999 and 2003. Main Outcome Measure  Death from any cause or new onset of congestive heart failure (CHF) through 2 years. Results  Levels of BNP were available in 4266 patients at study entry (prior to hospital discharge), 3618 patients at 4 months, and 2966 patients at 12 months. During follow-up there were 230 deaths and 163 incident cases of CHF. Adjusting for age, sex, index event, renal function, hypertension, prior heart failure, and diabetes, elevated levels of BNP (>80 pg/mL) were associated with subsequent death or new CHF when measured at study entry (111 [21%] vs 246 [7%]; adjusted hazard ratio [HR], 2.5; 95% confidence interval [CI], 2.0-3.3), at 4 months (34 [19%] vs 125 [4%]; adjusted HR, 3.9; 95% CI, 2.6-6.0), and at 12 months (19 [11%] vs 37 [1%]; adjusted HR, 4.7; 95% CI, 2.5-8.9). Patients with newly elevated levels of BNP at 4 months were at increased risk of death or new CHF (10 [15%] vs 105 [3%]); HR, 4.5; 95% CI, 2.3-8.6). Patients with elevated levels of BNP at study entry and with BNP levels lower than 80 pg/mL at 4 months tended to have only modestly increased risk (HR, 1.7; 95% CI, 1.0-2.9) compared with patients with BNP levels lower than 80 pg/mL at both visits. Conclusions  Serial determinations of BNP levels during outpatient follow-up after ACS predict the risk of death or new CHF. Changes in BNP levels over time are associated with long-term clinical outcomes and may provide a basis for enhanced clinical decision making in patients after onset of ACS. Clinical Trials Registration  ClinicalTrials.gov Identifier: NCT00251576      

Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial

Context  Defibrillation as soon as possible is standard treatment for patients with ventricular fibrillation. A nonrandomized study indicates that after a few minutes of ventricular fibrillation, delaying defibrillation to give cardiopulmonary resuscitation (CPR) first might improve the outcome. Objective  To determine the effects of CPR before defibrillation on outcome in patients with ventricular fibrillation and with response times either up to or longer than 5 minutes. Design, Setting, and Patients  Randomized trial of 200 patients with out-of-hospital ventricular fibrillation in Oslo, Norway, between June 1998 and May 2001. Patients received either standard care with immediate defibrillation (n = 96) or CPR first with 3 minutes of basic CPR by ambulance personnel prior to defibrillation (n = 104). If initial defibrillation was unsuccessful, the standard group received 1 minute of CPR before additional defibrillation attempts compared with 3 minutes in the CPR first group. Main Outcome Measure  Primary end point was survival to hospital discharge. Secondary end points were hospital admission with return of spontaneous circulation (ROSC), 1-year survival, and neurological outcome. A prespecified analysis examined subgroups with response times either up to or longer than 5 minutes. Results  In the standard group, 14 (15%) of 96 patients survived to hospital discharge vs 23 (22%) of 104 in the CPR first group (P = .17). There were no differences in ROSC rates between the standard group (56% [58/104]) and the CPR first group (46% [44/96]; P = .16); or in 1-year survival (20% [21/104] and 15% [14/96], respectively; P = .30). In subgroup analysis for patients with ambulance response times of either up to 5 minutes or shorter, there were no differences in any outcome variables between the CPR first group (n = 40) and the standard group (n = 41). For patients with response intervals of longer than 5 minutes, more patients achieved ROSC in the CPR first group (58% [37/64]) compared with the standard group (38% [21/55]; odds ratio [OR], 2.22; 95% confidence interval [CI], 1.06-4.63; P = .04); survival to hospital discharge (22% [14/64] vs 4% [2/55]; OR, 7.42; 95% CI, 1.61-34.3; P = .006); and 1-year survival (20% [13/64] vs 4% [2/55]; OR, 6.76; 95% CI, 1.42-31.4; P = .01). Thirty-three (89%) of 37 patients who survived to hospital discharge had no or minor reductions in neurological status with no difference between the groups. Conclusions  Compared with standard care for ventricular fibrillation, CPR first prior to defibrillation offered no advantage in improving outcomes for this entire study population or for patients with ambulance response times shorter than 5 minutes. However, the patients with ventricular fibrillation and ambulance response intervals longer than 5 minutes had better outcomes with CPR first before defibrillation was attempted. These results require confirmation in additional randomized trials.      

Effect of improving depression care on pain and functional outcomes among older adults with arthritis: a randomized controlled trial

Context  Depression and arthritis are disabling and common health problems in late life. Depression is also a risk factor for poor health outcomes among arthritis patients. Objective  To determine whether enhancing care for depression improves pain and functional outcomes in older adults with depression and arthritis. Design, Setting, and Participants  Preplanned subgroup analyses of Improving Mood-Promoting Access to Collaborative Treatment (IMPACT), a randomized controlled trial of 1801 depressed older adults (=" BORDER="0">60 years), which was performed at 18 primary care clinics from 8 health care organizations in 5 states across the United States from July 1999 to August 2001. A total of 1001 (56%) reported coexisting arthritis at baseline. Intervention  Antidepressant medications and/or 6 to 8 sessions of psychotherapy (Problem-Solving Treatment in Primary Care). Main Outcome Measures  Depression, pain intensity (scale of 0 to 10), interference with daily activities due to arthritis (scale of 0 to 10), general health status, and overall quality-of-life outcomes assessed at baseline, 3, 6, and 12 months. Results  In addition to reduction in depressive symptoms, the intervention group compared with the usual care group at 12 months had lower mean (SE) scores for pain intensity (5.62 [0.16] vs 6.15 [0.16]; between-group difference, -0.53; 95% confidence interval [CI], -0.92 to -0.14; P = .009), interference with daily activities due to arthritis (4.40 [0.18] vs 4.99 [0.17]; between-group difference, -0.59; 95% CI, -1.00 to -0.19; P = .004), and interference with daily activities due to pain (2.92 [0.07] vs 3.17 [0.07]; between-group difference, -0.26; 95% CI, -0.41 to -0.10; P = .002). Overall health and quality of life were also enhanced among intervention patients relative to control patients at 12 months. Conclusions  In a large and diverse population of older adults with arthritis (mostly osteoarthritis) and comorbid depression, benefits of improved depression care extended beyond reduced depressive symptoms and included decreased pain as well as improved functional status and quality of life.      

Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

Sonal Singh, MD, MPH; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD

JAMA. 2008;300(12):1439-1450.

Context  Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with chronic obstructive pulmonary disease (COPD) but their effect on the risk of cardiovascular outcomes is unknown.

Objective  To ascertain the cardiovascular risks of inhaled anticholinergics,including cardiovascular death, myocardial infarction (MI), and stroke.

Data Sources  Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews,regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.

Study Selection  Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.

Data Extraction  The primary outcome was a composite of cardiovascular death,MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed-effects models and statistical heterogeneity was estimated with the I² statistic.

Data Synthesis  After a detailed screening of 103 articles, 17 trials enrolling 14 783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7311 patients (1.2%) receiving control therapy (RR, 1.58 [95%confidence interval {CI}, 1.21-2.06]; P < .001,I² = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR, 1.53 [95% CI 1.05-2.23]; P = .03, I² = 0%) and cardiovascular death (RR, 1.80 [95% CI, 1.17-2.77]; P = .008,I² = 0%) without a statistically significant increase in the risk of stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20, I² = 0%).All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2.0%) and 115 of the control patients (1.6%)(RR, 1.26 [95% CI, 0.99-1.61]; P = .06,I² = 2%). A sensitivity analysis restricted to 5 long-term trials (>6 months) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics vs 1.8% of the control patients; RR, 1.73 [95%CI, 1.27-2.36]; P < .001, I² = 0%).

Conclusion  Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD.

     

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.      

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial

Context  Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. Objective  To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. Design, Setting, and Participants  The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. Main Outcome Measures  The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. Results  Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 µmol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. Conclusions  Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.      

Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study

Context  The Women's Health Initiative Memory Study (WHIMS) previously found increased risk for dementia and no effect on mild cognitive impairment (MCI) in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA). Objective  To determine the effects of CEE alone and CEE plus MPA on incidence of probable dementia and MCI in older women. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled clinical trials of CEE (estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in community-dwelling women aged 65 to 79 years, conducted from June 1995 to July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004 (estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers. Interventions  In the estrogen-alone trial, 1 daily tablet containing either 0.625 mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos. Main Outcome Measures  Probable dementia and MCI. Results  In the estrogen-alone trial, 47 participants were diagnosed with probable dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio [HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for probable dementia in the estrogen-alone trial were statistically similar to those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years for CEE plus MPA vs placebo, respectively; P = .11). When data were pooled per the original WHIMS protocol, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P = .005). After excluding participants with baseline Modified Mini-Mental State Examination scores at or below the screening cut point, the HR was 1.77 (95% CI, 0.74-4.23; P = .20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P = .006) in the pooled trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89). In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60). In the estrogen-alone trial, 93 participants receiving CEE were diagnosed with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95% CI, 1.01-1.89; P = .04). Conclusions  Estrogen therapy alone did not reduce dementia or MCI incidence and increased the risk for both end points combined. Pooling data for estrogen alone and estrogen plus progestin resulted in increased risks for both end points. Use of hormone therapy to prevent dementia or cognitive decline in women 65 years of age or older is not recommended.      

Long-term proton pump inhibitor therapy and risk of hip fracture

Context  Proton pump inhibitors (PPIs) may interfere with calcium absorption through induction of hypochlorhydria but they also may reduce bone resorption through inhibition of osteoclastic vacuolar proton pumps. Objective  To determine the association between PPI therapy and risk of hip fracture. Design, Setting, and Patients  A nested case-control study was conducted using the General Practice Research Database (1987-2003), which contains information on patients in the United Kingdom. The study cohort consisted of users of PPI therapy and nonusers of acid suppression drugs who were older than 50 years. Cases included all patients with an incident hip fracture. Controls were selected using incidence density sampling, matched for sex, index date, year of birth, and both calendar period and duration of up-to-standard follow-up before the index date. For comparison purposes, a similar nested case-control analysis for histamine 2 receptor antagonists was performed. Main Outcome Measure  The risk of hip fractures associated with PPI use. Results  There were 13 556 hip fracture cases and 135 386 controls. The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59). The risk of hip fracture was significantly increased among patients prescribed long-term high-dose PPIs (AOR, 2.65; 95% CI, 1.80-3.90; P<.001). The strength of the association increased with increasing duration of PPI therapy (AOR for 1 year, 1.22 [95% CI, 1.15-1.30]; 2 years, 1.41 [95% CI, 1.28-1.56]; 3 years, 1.54 [95% CI, 1.37-1.73]; and 4 years, 1.59 [95% CI, 1.39-1.80]; P<.001 for all comparisons). Conclusion  Long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.      

Hepatitis C virus seropositivity in organ donors and survival in heart transplant recipients

Context  Although liberalization of donor criteria could expand the donor pool, the use of certain "marginal donors," such as those who are hepatitis C virus (HCV) positive, is controversial. Little is known about the effect of donor HCV positivity on survival in cardiac transplantation. Objectives  To examine the association between donor HCV positivity and survival among heart transplant recipients and to determine the effects of recipient age and recipient HCV status on this association. Design, Setting, and Participants  A multicenter cohort study was performed using the US Scientific Registry of Transplant Recipients. Adult heart transplant patients who received their transplants between April 1, 1994, and July 31, 2003, were eligible for inclusion. Main Outcome Measure  All-cause mortality. Results  Of 10 915 patients meeting entry criteria, 261 received an HCV-positive donor heart. Mortality was higher among recipients of HCV-positive donor hearts at 1 year (16.9% vs 8.2%; P<.001), 5 years (41.8% vs 18.5%; P<.001), and 10 years (50.6% vs 24.3%; P<.001). Using Kaplan-Meier methods, 1-, 5-, and 10-year survival rates were 83%, 53%, and 25%, and 92%, 77%, and 53% for recipients of HCV-positive and HCV-negative donor hearts, respectively (P<.001, log-rank test). Recipients of HCV-positive donor hearts were more likely to die of liver disease and coronary vasculopathy. After propensity matching, the overall hazard ratio (HR) associated with receipt of an HCV-positive donor heart was 2.10 (95% confidence interval [CI], 1.60-2.75). Stratified analyses showed that HRs did not vary by recipient HCV status or by recipient age (for recipients aged 18-39 years: HR, 1.75 [95% CI, 0.70-4.40]; for recipients aged 40-59 years: HR, 2.23 [95% CI, 1.42-3.52]; and for recipients aged 60 years and older: HR, 2.07 [95% CI, 1.32-3.27]; overall P value for interaction, >.10). Conclusions  Receipt of a heart from an HCV-positive donor is associated with decreased survival in heart transplant recipients. This association appears to be independent of recipient HCV status and age. Preferential allocation of HCV-positive donors to HCV-positive recipients and/or older recipients is not warranted.      

Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study

Context  The benefit of clopidogrel pretreatment before percutaneous coronary intervention (PCI) remains debated and its use has not been universally adopted. Objective  To determine if clopidogrel pretreatment before PCI in patients with recent ST-segment elevation myocardial infarction (STEMI) is superior to clopidogrel treatment initiated at the time of PCI in preventing major adverse cardiovascular events. Design, Setting, and Participants  The PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) study was a prospectively planned analysis of the 1863 patients undergoing PCI after mandated angiography in CLARITY–Thrombolysis in Myocardial Infarction (TIMI) 28, a randomized, double-blind, placebo-controlled trial of clopidogrel in patients receiving fibrinolytics for STEMI. Patients were enrolled at 319 sites in 23 countries from February 2003 through October 2004. Interventions  Patients received aspirin and were randomized to receive either clopidogrel (300 mg loading dose, then 75 mg once daily) or placebo initiated with fibrinolysis and given until coronary angiography, which was performed 2 to 8 days after initiation of the study drug. For patients undergoing coronary artery stenting, it was recommended that open-label clopidogrel (including a loading dose) be administered after the diagnostic angiogram. Main Outcome Measures  The primary outcome was the incidence of the composite of cardiovascular death, recurrent MI, or stroke from PCI to 30 days after randomization. Secondary outcomes included MI or stroke before PCI and the aforementioned composite from randomization to 30 days. Results  Pretreatment with clopidogrel significantly reduced the incidence of cardiovascular death, MI, or stroke following PCI (34 [3.6%] vs 58 [6.2%]; adjusted odds ratio [OR], 0.54 [95% CI, 0.35-0.85]; P = .008). Pretreatment with clopidogrel also reduced the incidence of MI or stroke prior to PCI (37 [4.0%] vs 58 [6.2%]; OR, 0.62 [95% CI, 0.40-0.95]; P = .03). Overall, pretreatment with clopidogrel resulted in a highly significant reduction in cardiovascular death, MI, or stroke from randomization through 30 days (70 [7.5%] vs 112 [12.0%]; adjusted OR, 0.59 [95% CI, 0.43-0.81]; P = .001; number needed to treat = 23). There was no significant excess in the rates of TIMI major or minor bleeding (18 [2.0%] vs 17 [1.9%]; P>.99). Conclusions  Clopidogrel pretreatment significantly reduces the incidence of cardiovascular death or ischemic complications both before and after PCI and without a significant increase in major or minor bleeding. These data add further support to the early use of clopidogrel in STEMI and the strategy of routine clopidogrel pretreatment in patients undergoing PCI.      

6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial

Context  Survival benefit in the management of high-grade clinically localized prostate cancer has been shown for 70 Gy radiation therapy combined with 3 years of androgen suppression therapy (AST), but long-term AST is associated with many adverse events. Objective  To assess the survival benefit of 3-dimensional conformal radiation therapy (3D-CRT) alone or in combination with 6 months of AST in patients with clinically localized prostate cancer. Design, Setting, and Patients  A prospective randomized controlled trial of 206 patients with clinically localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone (n = 104) or in combination with 6 months of AST (n = 102) from December 1, 1995, to April 15, 2001. Eligible patients included those with a prostate-specific antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extraprostatic disease. Main Outcome Measures  Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive visits) and overall survival. Results  After a median follow-up of 4.52 years, patients randomized to receive 3D-CRT plus AST had a significantly higher survival (P = .04), lower prostate cancer–specific mortality (P = .02), and higher survival free of salvage AST (P = .002). Kaplan-Meier estimates of 5-year survival rates were 88% (95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78% (95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57% (95% CI, 46%-69%) in the 3D-CRT group. Conclusion  The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival benefit for patients with clinically localized prostate cancer.      

Burden, features, and outcome of neurological involvement in acute falciparum malaria in Kenyan children

Context  Plasmodium falciparum appears to have a particular propensity to involve the brain but the burden, risk factors, and full extent of neurological involvement have not been systematically described. Objectives  To determine the incidence and describe the clinical phenotypes and outcomes of neurological involvement in African children with acute falciparum malaria. Design, Setting, and Patients  A review of records of all children younger than 14 years admitted to a Kenyan district hospital with malaria from January 1992 through December 2004. Neurological involvement was defined as convulsive seizures, agitation, prostration, or impaired consciousness or coma. Main Outcome Measures  The incidence, pattern, and outcome of neurological involvement. Results  Of 58 239 children admitted, 19 560 (33.6%) had malaria as the primary clinical diagnosis. Neurological involvement was observed in 9313 children (47.6%) and manifested as seizures (6563/17 517 [37.5%]), agitation (316/11 193 [2.8%]), prostration (3223/15 643 [20.6%]), and impaired consciousness or coma (2129/16 080 [13.2%]). In children younger than 5 years, the mean annual incidence of admissions with malaria was 2694 per 100 000 persons and the incidence of malaria with neurological involvement was 1156 per 100 000 persons. However, readmissions may have led to a 10% overestimate in incidence. Children with neurological involvement were older (median, 26 [interquartile range {IQR}, 15-41] vs 21 [IQR, 10-40] months; P<.001), had a shorter duration of illness (median, 2 [IQR, 1-3] vs 3 [IQR, 2-3] days; P<.001), and a higher geometric mean parasite density (42.0 [95% confidence interval {CI}, 40.0-44.1] vs 30.4 [95% CI, 29.0-31.8] x 10³/µL; P<.001). Factors independently associated with neurological involvement included past history of seizures (adjusted odds ratio [AOR], 3.50; 95% CI, 2.78-4.42), fever lasting 2 days or less (AOR, 2.02; 95% CI, 1.64-2.49), delayed capillary refill time (AOR, 3.66; 95% CI, 2.40-5.56), metabolic acidosis (AOR, 1.55; 95% CI, 1.29-1.87), and hypoglycemia (AOR, 2.11; 95% CI, 1.31-3.37). Mortality was higher in patients with neurological involvement (4.4% [95% CI, 4.2%-5.1%] vs 1.3% [95% CI, 1.1%-1.5%]; P<.001). At discharge, 159 (2.2%) of 7281 patients had neurological deficits. Conclusions  Neurological involvement is common in children in Kenya with acute falciparum malaria, and is associated with metabolic derangements, impaired perfusion, parasitemia, and increased mortality and neurological sequelae. This study suggests that falciparum malaria exposes many African children to brain insults.      

Evaluation of restorative care vs usual care for older adults receiving an acute episode of home care

Context  Illness and hospitalization often trigger functional decline among older persons. Home care services implemented for functional decline provide an opportunity to intervene to improve outcomes. Objective  To compare functional status and the likelihood of remaining at home for persons receiving restorative care vs usual home care. Design and Setting  Intervention using prospective individual matching conducted between November 1, 1998, and April 30, 2000. Six offices of a home care agency in Connecticut were used. One branch office served as the restorative care unit and the other 5 served as usual care offices. Participants  Patients receiving home care through the restorative care office who were 65 years or older; in receipt of Medicare-covered home care lasting at least 7 days; with absence of severe cognitive impairment; and not terminal, bedridden, or requiring total care were matched with patients from 1 of the usual care offices. The matching factors included age, sex, race, baseline self-care function, cognitive status, whether hospitalization preceded the home care episode, and date of the home care episode. Of the 712 eligible restorative care patients, 691 (97%) were matched with a usual care patient. Intervention  Restorative care, provided by the home care agency nursing, therapy, and home health aide staff, was based on principles from geriatric medicine, nursing, rehabilitation, and goal attainment. Main Outcome Measures  Remaining at home, functional status at completion of the home care episode, and duration and intensity of home care episode. Results  Compared with usual care, and after adjusting for baseline characteristics and other factors, restorative care was associated with a greater likelihood of remaining at home (82% vs 71%; odds ratio [OR], 1.99; 95% confidence interval [CI], 1.47-2.69) and a reduced likelihood of visiting an emergency department (10% vs 20%; OR, 0.44; 95% CI, 0.32-0.61). Home care episodes were shorter (mean [SD], 24.8 [26.8] days vs 34.3 [44.2] days; S = -17 821; P<.001). Restorative care patients had better mean (SD) scores than usual care patients in self-care (11.0 [2.1] vs 10.7 [2.5]; P = .07 after adjustment), home management (9.5 [2.9] vs 9.2 [3.0]; P = .05 after adjustment), and mobility (3.3 [0.8] vs 3.2 [0.9]; P = .02 after adjustment). Conclusions  This trial suggests that reorganizing the structure and goals of home care can enhance health outcomes of older patients without increasing health care utilization.