Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial

Context  Reduced growth hormone (GH) concentrations are observed in men with human immunodeficiency virus (HIV) lipodystrophy. Objective  To investigate the effects of growth hormone–releasing hormone (GHRH), a GH secretagogue, in treatment of HIV lipodystrophy. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted at a research center in the United States between October 2002 and June 2003 and enrolling 31 HIV-infected men aged 18 to 60 years with evidence of lipodystrophy. Interventions  Participants were assigned to receive GHRH (1 mg subcutaneously twice daily) or placebo for 12 weeks. Main Outcome Measures  The primary outcome was change in concentrations of insulin-like growth factor 1 (IGF-1) to detect overall change in GH levels in response to GHRH. Secondary end points included body composition by dual-energy x-ray absorptiometry and computed tomography, lipodystrophy ratings, and levels of glucose, insulin, and lipids. Results  Mean (SD) IGF-1 concentrations increased significantly in the GHRH group vs the placebo group (104 [110] ng/mL vs 6 [44] ng/mL, P = .004). Lean body mass significantly increased in the GHRH group vs the placebo group (0.9 [1.3] kg vs –0.3 [1.7] kg, P = .04), trunk fat significantly decreased (–0.4 [0.7] kg vs 0.2 [0.6] kg, P = .03), and the ratio of trunk to lower extremity fat improved significantly (–0.22 [0.32] vs 0.14 [0.29], P = .005). Abdominal visceral fat was reduced (–19.2 [36.6] cm² vs 2.3 [24.3] cm², P = .07) and the ratio of abdominal visceral fat to abdominal subcutaneous fat improved significantly more in the GHRH group (–0.19 [0.28] vs 0.07 [0.27], P = .02). Both physician and patient rating of lipodystrophy in the arms, legs, and abdomen also improved significantly. Levels of glucose, insulin, and lipids did not change significantly. Conclusions  GHRH was well tolerated and effectively increased levels of IGF-1 in HIV-infected men with lipodystrophy. Total and regional body composition improved in response to GHRH, with increased lean mass and reduced truncal and visceral fat. Use of GHRH may potentially be a beneficial treatment strategy for this population.      

Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial

Context  Cardiac resynchronization therapy (CRT) through biventricular pacing is an effective treatment for heart failure (HF) with a wide QRS; however, the outcomes of patients requiring CRT and implantable cardioverter defibrillator (ICD) therapy are unknown. Objective  To examine the efficacy and safety of combined CRT and ICD therapy in patients with New York Heart Association (NYHA) class III or IV congestive HF despite appropriate medical management. Design, Setting, and Participants  Randomized, double-blind, parallel-controlled trial conducted from October 1, 1999, to August 31, 2001, of 369 patients with left ventricular ejection fraction of 35% or less, QRS duration of 130 ms, at high risk of life-threatening ventricular arrhythmias, and in NYHA class III (n = 328) or IV (n = 41) despite optimized medical treatment. Interventions  Of 369 randomized patients who received devices with combined CRT and ICD capabilities, 182 were controls (ICD activated, CRT off) and 187 were in the CRT group (ICD activated, CRT on). Main Outcome Measures  The primary double-blind study end points were changes between baseline and 6 months in quality of life, functional class, and distance covered during a 6-minute walk. Additional outcome measures included changes in exercise capacity, plasma neurohormones, left ventricular function, and overall HF status. Survival, incidence of ventricular arrhythmias, and rates of hospitalization were also compared. Results  At 6 months, patients assigned to CRT had a greater improvement in median (95% confidence interval) quality of life score (–17.5 [–21 to –14] vs –11.0 [–16 to –7], P = .02) and functional class (–1 [–1 to –1] vs 0 [–1 to 0], P = .007) than controls but were no different in the change in distance walked in 6 minutes (55 m [44-79] vs 53 m [43-75], P = .36). Peak oxygen consumption increased by 1.1 mL/kg per minute (0.7-1.6) in the CRT group vs 0.1 mL/kg per minute (–0.1 to 0.8) in controls (P = .04), although treadmill exercise duration increased by 56 seconds (30-79) in the CRT group and decreased by 11 seconds (–55 to 12) in controls (P<.001). No significant differences were observed in changes in left ventricular size or function, overall HF status, survival, and rates of hospitalization. No proarrhythmia was observed and arrhythmia termination capabilities were not impaired. Conclusions  Cardiac resynchronization improved quality of life, functional status, and exercise capacity in patients with moderate to severe HF, a wide QRS interval, and life-threatening arrhythmias. These improvements occurred in the context of underlying appropriate medical management without proarrhythmia or compromised ICD function.      

Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model

Context  Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined. Objective  To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model. Design, Setting, and Participants  Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E^–/– (apoE^–/–) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 µm (PM_2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months. Main Outcome Measures  Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes. Results  In the high-fat chow group, the mean (SD) composite plaque area of PM_2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM_2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM_2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10^-8 vs 4.3 [0.1] x 10^-8, respectively; P = .04). Mice fed high-fat chow and exposed to PM_2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001). Conclusion  In an apoE^–/– mouse model, long-term exposure to low concentration of PM_2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.      

Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss

Context  Weight loss elicits physiological adaptations relating to energy intake and expenditure that antagonize ongoing weight loss. Objective  To test whether dietary composition affects the physiological adaptations to weight loss, as assessed by resting energy expenditure. Design, Study, and Participants  A randomized parallel-design study of 39 overweight or obese young adults aged 18 to 40 years who received an energy-restricted diet, either low–glycemic load or low-fat. Participants were studied in the General Clinical Research Centers of the Brigham and Women’s Hospital and the Children’s Hospital, Boston, Mass, before and after 10% weight loss. The study was conducted from January 4, 2001, to May 6, 2003. Main Outcome Measures  Resting energy expenditure measured in the fasting state by indirect calorimetry, body composition by dual-energy x-ray absorptiometry, cardiovascular disease risk factors, and self-reported hunger. Results  Resting energy expenditure decreased less with the low–glycemic load diet than with the low-fat diet, expressed in absolute terms (mean [SE], 96 [24] vs 176 [27] kcal/d; P = .04) or as a proportion (5.9% [1.5%] vs 10.6% [1.7%]; P = .05). Participants receiving the low–glycemic load diet reported less hunger than those receiving the low-fat diet (P = .04). Insulin resistance (P = .01), serum triglycerides (P = .01), C-reactive protein (P = .03), and blood pressure (P = .07 for both systolic and diastolic) improved more with the low–glycemic load diet. Changes in body composition (fat and lean mass) in both groups were very similar (P = .85 and P = .45, respectively). Conclusions  Changes in dietary composition within prevailing norms can affect physiological adaptations that defend body weight. Reduction in glycemic load may aid in the prevention or treatment of obesity, cardiovascular disease, and diabetes mellitus.      

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.      

Transition of extremely low-birth-weight infants from adolescence to young adulthood: comparison with normal birth-weight controls

Context  Traditionally, educational attainment, getting a job, living independently, getting married, and parenthood have been considered as markers of successful transition to adulthood. Objective  To describe and compare the achievement and the age at attainment of the above markers between extremely low-birth-weight (ELBW) and normal birth-weight (NBW) young adults. Design, Setting, and Participants  A prospective, longitudinal, population-based study in central-west Ontario, Canada, of 166 ELBW participants who weighed 501 to 1000 g at birth (1977-1982) and 145 sociodemographically comparable NBW participants assessed at young adulthood (22-25 years). Interviewers masked to participant status administered validated questionnaires via face-to-face interviews between January 1, 2002, and April 30, 2004. Main Outcome Measures  Markers of successful transition to adulthood, including educational attainment, student and/or worker role, independent living, getting married, and parenthood. Results  At young adulthood, 149 (90%) of 166 ELBW participants and 133 (92%) of 145 NBW participants completed the assessments at mean (SD) age of 23.3 (1.2) years and 23.6 (1.1) years, respectively. We included participants with neurosensory impairments (ELBW vs NBW: 40 [27%] vs 3 [2%]) and 7 proxy respondents. The proportion who graduated from high school was similar (82% vs 87%, P = .21). Overall, no statistically significant differences were observed in the education achieved to date. A substantial proportion of both groups were still pursuing postsecondary education (47 [32%] vs 44 [33%]). No significant differences were observed in employment/school status; 71 (48%) ELBW vs 76 (57%) NBW young adults were permanently employed (P = .09). In a subanalysis, a higher proportion of ELBW young adults were neither employed nor in school (39 [26%] vs 20 [15%], P = .02 by Holm's correction); these differences did not persist when participants with disabilities were excluded. No significant differences were found in the proportion living independently (63 [42%] vs 70 [53%], P = .19), married/cohabitating (34 [23%] vs 33 [25%], P = .69), or who were parents (16 [11%] vs 19 [14%], P = .36). The age at attainment of the above markers was similar for both cohorts. Conclusion  Our study results indicate that a significant majority of former ELBW infants have overcome their earlier difficulties to become functional young adults.      

Patterns of functional decline at the end of life

Context  Clinicians have observed various patterns of functional decline at the end of life, but few empirical data have tested these patterns in large populations. Objective  To determine if functional decline differs among 4 types of illness trajectories: sudden death, cancer death, death from organ failure, and frailty. Design, Setting, and Participants  Cohort analysis of data from 4 US regions in the prospective, longitudinal Established Populations for Epidemiologic Studies of the Elderly (EPESE) study. Of the 14 456 participants aged 65 years or older who provided interviews at baseline (1981-1987), 4871 died during the first 6 years of follow-up; 4190 (86%) of these provided interviews within 1 year before dying. These decedents were evenly distributed in 12 cohorts based on the number of months between the final interview and death. Main Outcome Measures  Self- or proxy-reported physical function (performance of 7 activities of daily living [ADLs]) within 1 year prior to death; predicted ADL dependency prior to death. Results  Mean function declined across the 12 cohorts, simulating individual decline in the final year of life. Sudden death decedents were highly functional even in the last month before death (mean [95% confidence interval {CI}] numbers of ADL dependencies: 0.69 [0.19-1.19] at 12 months before death vs 1.22 [0.59-1.85] at the final month of life, P = .20); cancer decedents were highly functional early in their final year but markedly more disabled 3 months prior to death (0.77 [0.30-1.24] vs 4.09 [3.37-4.81], P<.001); organ failure decedents experienced a fluctuating pattern of decline, with substantially poorer function during the last 3 months before death (2.10 [1.49-2.70] vs 3.66 [2.94-4.38], P<.001); and frail decedents were relatively more disabled in the final year and especially dependent during the last month (2.92 [2.24-3.60] vs 5.84 [5.33-6.35], P<.001). After controlling for age, sex, race, education, marital status, interval between final interview and death, and other demographic differences, frail decedents were more than 8 times more likely than sudden death decedents to be ADL dependent (OR, 8.32 [95% CI, 6.46-10.73); cancer decedents, one and a half times more likely (OR, 1.57 [95% CI, 1.25-1.96]); and organ failure decedents, 3 times more likely (OR, 3.00 [95% CI, 2.39-3.77]). Conclusions  Trajectories of functional decline at the end of life are quite variable. Differentiating among expected trajectories and related needs would help shape tailored strategies and better programs of care prior to death.      

Effectiveness of a quality improvement intervention for adolescent depression in primary care clinics: a randomized controlled trial

Context  Depression is a common condition associated with significant morbidity in adolescents. Few depressed adolescents receive effective treatment for depression in primary care settings. Objective  To evaluate the effectiveness of a quality improvement intervention aimed at increasing access to evidence-based treatments for depression (particularly cognitive-behavior therapy and antidepressant medication), relative to usual care, among adolescents in primary care practices. Design, Setting, and Participants  Randomized controlled trial conducted between 1999 and 2003 enrolling 418 primary care patients with current depressive symptoms, aged 13 through 21 years, from 5 health care organizations purposively selected to include managed care, public sector, and academic medical center clinics in the United States. Intervention  Usual care (n = 207) or 6-month quality improvement intervention (n = 211) including expert leader teams at each site, care managers who supported primary care clinicians in evaluating and managing patients’ depression, training for care managers in manualized cognitive-behavior therapy for depression, and patient and clinician choice regarding treatment modality. Participating clinicians also received education regarding depression evaluation, management, and pharmacological and psychosocial treatment. Main Outcome Measures  Depressive symptoms assessed by Center for Epidemiological Studies-Depression Scale (CES-D) score. Secondary outcomes were mental health–related quality of life assessed by Mental Health Summary Score (MCS-12) and satisfaction with mental health care assessed using a 5-point scale. Results  Six months after baseline assessments, intervention patients, compared with usual care patients, reported significantly fewer depressive symptoms (mean [SD] CES-D scores, 19.0 [11.9] vs 21.4 [13.1]; P = .02), higher mental health–related quality of life (mean [SD] MCS-12 scores, 44.6 [11.3] vs 42.8 [12.9]; P = .03), and greater satisfaction with mental health care (mean [SD] scores, 3.8 [0.9] vs 3.5 [1.0]; P = .004). Intervention patients also reported significantly higher rates of mental health care (32.1% vs 17.2%, P<.001) and psychotherapy or counseling (32.0% vs 21.2%, P = .007). Conclusions  A 6-month quality improvement intervention aimed at improving access to evidence-based depression treatments through primary care was significantly more effective than usual care for depressed adolescents from diverse primary care practices. The greater uptake of counseling vs medication under the intervention reinforces the importance of practice interventions that include resources to enable evidence-based psychotherapy for depressed adolescents.      

Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial

Context  Observational studies have shown that psychosocial factors are associated with increased risk for cardiovascular morbidity and mortality, but the effects of behavioral interventions on psychosocial and medical end points remain uncertain. Objective  To determine the effect of 2 behavioral programs, aerobic exercise training and stress management training, with routine medical care on psychosocial functioning and markers of cardiovascular risk. Design, Setting, and Patients  Randomized controlled trial of 134 patients (92 male and 42 female; aged 40-84 years) with stable ischemic heart disease (IHD) and exercise-induced myocardial ischemia. Conducted from January 1999 to February 2003. Interventions  Routine medical care (usual care); usual care plus supervised aerobic exercise training for 35 minutes 3 times per week for 16 weeks; usual care plus weekly 1.5-hour stress management training for 16 weeks. Main Outcome Measures  Self-reported measures of general distress (General Health Questionnaire [GHQ]) and depression (Beck Depression Inventory [BDI]); left ventricular ejection fraction (LVEF) and wall motion abnormalities (WMA); flow-mediated dilation; and cardiac autonomic control (heart rate variability during deep breathing and baroreflex sensitivity). Results  Patients in the exercise and stress management groups had lower mean (SE) BDI scores (exercise: 8.2 [0.6]; stress management: 8.2 [0.6]) vs usual care (10.1 [0.6]; P = .02); reduced distress by GHQ scores (exercise: 56.3 [0.9]; stress management: 56.8 [0.9]) vs usual care (53.6 [0.9]; P = .02); and smaller reductions in LVEF during mental stress testing (exercise: –0.54% [0.44%]; stress management: –0.34% [0.45%]) vs usual care (–1.69% [0.46%]; P = .03). Exercise and stress management were associated with lower mean (SE) WMA rating scores (exercise: 0.20 [0.07]; stress management: 0.10 [0.07]) in a subset of patients with significant stress-induced WMA at baseline vs usual care (0.36 [0.07]; P = .02). Patients in the exercise and stress management groups had greater mean (SE) improvements in flow-mediated dilation (exercise: mean [SD], 5.6% [0.45%]; stress management: 5.2% [0.47%]) vs usual care patients (4.1% [0.48%]; P = .03). In a subgroup, those receiving stress management showed improved mean (SE) baroreflex sensitivity (8.2 [0.8] ms/mm Hg) vs usual care (5.1 [0.9] ms/mm Hg; P = .02) and significant increases in heart rate variability (193.7 [19.6] ms) vs usual care (132.1 [21.5] ms; P = .04). Conclusion  For patients with stable IHD, exercise and stress management training reduced emotional distress and improved markers of cardiovascular risk more than usual medical care alone.      

Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement: a randomized controlled trial

Context  Controlling postoperative pain after knee replacement while reducing opiod-induced adverse effects and improving outcomes remains an important challenge. Objective  To assess the effect of combined preoperative and postoperative administration of a selective inhibitor of cyclooxygenase 2 on opioid consumption and outcomes after total knee arthroplasty (TKA). Design, Setting, and Patients  Randomized, placebo-controlled, double-blind trial conducted June 2001 through September 2002, enrolling 70 patients aged 40 to 77 years and undergoing TKA at a university hospital in the United States. Interventions  Patients were randomly assigned to receive 50 mg of oral rofecoxib at 24 hours and at 1 to 2 hours before TKA, 50 mg daily for 5 days postoperatively, and 25 mg daily for another 8 days, or matching placebo at the same times. Main Outcome Measures  Postoperative outcomes including postsurgical analgesic consumption and pain scores achieved, nausea and vomiting, joint range of motion, sleep disturbance, patient satisfaction with analgesia, and hematologic and coagulation parameters. Results  Total epidural analgesic consumption and in-hospital opioid consumption were less in the group receiving rofecoxib compared with the group receiving placebo (P<.05). Median pain score (visual analog scale [VAS], 0-10) achieved for the knee was lower in the rofecoxib group compared with the placebo group during hospital stay (2.2 [interquartile range {IQR}, 1.4-3.2] vs 3.5 [IQR, 2.7-4.3], P<.001) and 1 week after discharge (2.6 [IQR, 1.4-3.5] vs 3.7 [IQR, 2.9-4.7], P = .03). There was less postoperative vomiting in the rofecoxib group (6%) compared with the placebo group (26%) (P = .047), as well as a decrease in sleep disturbance compared with the placebo group on the night of surgery (P = .006) and on the first (P = .047) and second (P<.001) days postoperatively. Knee flexion was increased in the rofecoxib group compared with the placebo group at discharge (active flexion: mean [SD], 84.2° [11.1°] vs 73.2° [13.6°], P = .03; passive flexion: 90.5° [6.8°] vs 81.8° [13.4°], P = .05) and at 1 month postoperatively (109.3° [8.5°] vs 100.8° [11.8°], P = .01), with shorter time in physical therapy to achieve effective joint range of motion. The rofecoxib group was more satisfied with analgesia and anesthesia at discharge compared with the placebo group (median satisfaction score, 4.3 [IQR, 3.0-4.7] vs 3.3 [IQR, 2.3-4.3], respectively; P = .03), and the differences persisted at 2-week and at 1-month follow-up. There was no intergroup difference in surgical blood loss (P>.05 for both intraoperative and postoperative blood loss). Conclusion  Perioperative use of an inhibitor of cyclooxygenase 2 is an effective component of multimodal analgesia that reduces opioid consumption, pain, vomiting, and sleep disturbance, with improved knee range of motion after TKA.      

Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial

Context  In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known. Objective  To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning. Design, Setting, and Patients  Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded. Intervention  Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines. Main Outcome Measure  Ventilator-free days to day 28. Results  The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, –0.2 days; 95% CI, –3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, –3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure–free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28. Conclusion  Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.      

Treatment of acne vulgaris with a pulsed dye laser: a randomized controlled trial

Context  The high prevalence of acne vulgaris and its significant morbidity underscore the need for convenient, low-risk, and efficacious therapy. Treatment with various lasers has been reported to improve acne. Objective  To evaluate the clinical efficacy of pulsed dye laser therapy in the treatment of acne. Design, Setting, and Patients  Randomized, single-blind, controlled, split-face clinical trial of a volunteer sample of 40 patients aged 13 years or older with facial acne conducted at an academic referral center from August 2002 to September 2003. Intervention  One or 2 nonpurpuric pulsed dye laser treatments to half of the face (fluence of 3 J/cm²), serial blinded clinical assessments (lesion counts), and grading of acne severity using standardized bilateral serial photographs. Main Outcome Measures  Comparison of the changes in lesion counts from baseline to 12 weeks between treated and untreated sides of the face and changes in photographic evidence of acne severity as graded by a panel of dermatologists blinded to treatment assignment. Results  After 12 weeks, using intent-to-treat analysis with last observation carried forward, there were no significant differences between laser-treated and untreated skin for changes in mean papule counts (–4.2 vs –2.2; P = .08), mean pustule counts (0 vs –1.0; P = .12), or mean comedone counts (2.9 vs 1.6; P = .63). Grading of serial photographs confirmed the clinical assessments, showing no significant mean (SE) differences in Leeds scores (range, 1-12) for treated skin (3.98 [0.32] at baseline and 3.94 [0.27] at week 12) compared with untreated skin (3.83 [0.32] at baseline and 3.79 [0.28] at week 12) (P>.99). Conclusions  In this study, the nonpurpuric pulsed dye laser therapy did not result in significant improvement of facial acne. More research is needed before this laser therapy may be recommended as an acne treatment.      

Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial

Context  Atherosclerosis is often advanced before symptoms appear and it is not clear whether treatment is beneficial in middle-aged individuals with a low Framingham risk score (FRS) and mild to moderate subclinical atherosclerosis. Objective  To assess whether statin therapy could slow progression and/or cause regression of carotid intima-media thickness (CIMT) over 2 years. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled study (Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin [METEOR]) of 984 individuals, with either age (mean, 57 years) as the only coronary heart disease risk factor or a 10-year FRS of less than 10%, modest CIMT thickening (1.2-<3.5 mm), and elevated LDL cholesterol (mean, 154 mg/dL); conducted at 61 primary care centers in the United States and Europe between August 2002 and May 2006. Intervention  Participants received either a 40-mg dose of rosuvastatin or placebo. Main Outcome Measures  Rate of change in maximum CIMT (assessed with B-mode ultrasound) for 12 carotid sites; changes in maximum CIMT of the common carotid artery, carotid bulb, and internal carotid artery sites and in mean CIMT of the common carotid artery sites. CIMT regression was assessed in the rosuvastatin group only. Results  Among participants in the rosuvastatin group, the mean (SD) baseline LDL cholesterol level of 155 (24.1) mg/dL declined to 78 (27.5) mg/dL, a mean reduction of 49% (P<.001 vs placebo group). The change in maximum CIMT for the 12 carotid sites was –0.0014 (95% CI, –0.0041 to 0.0014) mm/y for the rosuvastatin group vs 0.0131 (95% CI, 0.0087-0.0174) mm/y for the placebo group (P<.001). The change in maximum CIMT for the rosuvastatin group was –0.0038 (95% CI, –0.0064 to –0.0013) mm/y for the common carotid artery sites (P<.001), –0.0040 (95% CI, –0.0090 to 0.0010) mm/y for the carotid bulb sites (P<.001), and 0.0039 (95% CI, –0.0009 to 0.0088) mm/y for the internal carotid artery sites (P = .02). The change in mean CIMT for the rosuvastatin group for the common carotid artery sites was 0.0004 (95% CI, –0.0011 to 0.0019) mm/y (P<.001). All P values are vs placebo group. Overall, rosuvastatin was well tolerated with infrequent serious adverse cardiovascular events (6 participants [0.86%] had 8 events [1.1%] over 2 years). Conclusions  In middle-aged adults with an FRS of less than 10% and evidence of subclinical atherosclerosis, rosuvastatin resulted in statistically significant reductions in the rate of progression of maximum CIMT over 2 years vs placebo. Rosuvastatin did not induce disease regression. Larger, longer-term trials are needed to determine the clinical implications of these findings. Trial Registration  clinicaltrials.gov Identifier: NCT00225589      

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.      

Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials

Context  Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V₂-receptor antagonist, shows promise in this condition. Objective  To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure. Design, Setting, and Patients  Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied. Intervention  Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission. Main Outcome Measures  Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge). Results  Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension. Conclusion  In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events. Trial Registration  clinicaltrials.gov Identifier: NCT00071331      

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      

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial

Context  Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. Objective  To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. Design, Setting, and Patients  Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. Interventions  Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n = 839) and study completion (n = 676). Main Outcome Measures  The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). Results  In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (–0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P = .22), respectively, and TAV decreased 2.2 mm³ (–4.09 to –0.24) vs an increase of 0.88 mm³ (–1.03 to 2.79) (P = .03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (–0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P = .13), and TAV decreased 1.95 mm³ (–3.8 to –0.10) vs an increase of 1.19 mm³ (–0.73 to 3.12) (P = .02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [–5.1 to –3.5] vs 0.5 kg [–1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [–5.4 to –3.7] vs 1.0 cm [–1.9 to –0.2]) (P < .001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8 mg/dL (4.9 to 6.8) (22.4%) vs 1.8 mg/dL (0.9 to 2.7) (6.9%) (P < .001), and median triglyceride levels decreased 24.8 mg/dL (–35.4 to –17.3) (20.5%) vs 8.9 mg/dL (–14.2 to –1.8) (6.2%) (P < .001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [–1.7 to –1.2] [50.3%] vs 0.9 mg/dL [–1.4 to –0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11% [0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P < .001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P < .001). Conclusions  After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. Trial Registration  clinicaltrials.gov Identifier: NCT00124332      

Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial

Context  Many physicians believe that the pulmonary artery catheter (PAC) is useful for the diagnosis and treatment of cardiopulmonary disturbances; however, observational studies suggest that its use may be harmful. Objective  To determine the effects on outcome of the early use of a PAC in patients with shock mainly of septic origin, acute respiratory distress syndrome (ARDS), or both. Design, Setting, and Patients  A multicenter randomized controlled study of 676 patients aged 18 years or older who fulfilled the standard criteria for shock, ARDS, or both conducted in 36 intensive care units in France from January 30, 1999, to June 29, 2001. Intervention  Patients were randomly assigned to either receive a PAC (n = 335) or not (n = 341). The treatment was left to the discretion of each individual physician. Main Outcome Measures  The primary end point was mortality at 28 days. The principal secondary end points were day 14 and 90 mortality; day 14 organ system, renal support, and vasoactive agents–free days; hospital, intensive care unit, and mechanical ventilation–free days at day 28. Results  The 2 groups were similar at baseline. There were no significant differences in mortality with or without the PAC at day 14: 49.9% vs 51.3% (mortality relative risk [RR], 0.97; 95% confidence interval [CI], 0.84-1.13; P = .70); day 28: 59.4% vs 61.0% (RR, 0.97; 95% CI, 0.86-1.10; P = .67); or day 90: 70.7% vs 72.0% (RR, 0.98; 95% CI, 0.89-1.08; P = .71). At day 14, the mean (SD) number of days free of organ system failures with or without the PAC (2.3 [3.6] vs 2.4 [3.5]), renal support (7.4 [6.0] vs 7.5 [5.9]), and vasoactive agents (3.8 [4.8] vs 3.9 [4.9]) did not differ. At day 28, mean (SD) days in hospital with or without the PAC (0.9 [3.6] vs 0.9 [3.3]), in the intensive care unit (3.4 [6.8] vs 3.3 [6.9]), or mechanical ventilation use (5.2 [8.5] vs 5.0 [8.5]) did not differ. Conclusion  Clinical management involving the early use of a PAC in patients with shock, ARDS, or both did not significantly affect mortality and morbidity.      

Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial

Context  Aortic stiffness is increased in Marfan syndrome contributing to aortic dilatation and rupture, the major cause of premature death in this population. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness. Objective  To determine whether perindopril therapy reduces aortic stiffness and attenuates aortic dilatation in patients with Marfan syndrome. Design, Setting, and Participants  A randomized, double-blind, placebo-controlled trial of 17 patients with Marfan syndrome (mean [SD], 33 [6] years) taking standard -blocker therapy, initiated in January 2004 and completed in September 2006, at Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia. Intervention  Patients were administered 8 mg/d of perindopril (n = 10) or placebo (n = 7) for 24 weeks. Main Outcome Measures  Indices of arterial stiffness were assessed via systemic arterial compliance, and central and peripheral pulse wave velocities. Aortic root diameters were assessed at 4 sites via transthoracic echocardiography. Results  Perindopril reduced arterial stiffness as indicated by increased systemic arterial compliance (mean [SEM], 0.33 [0.01] mL/mm Hg at baseline to 0.54 [0.04] mL/mm Hg at 24 weeks in perindopril group vs 0.30 [0.01] mL/mm Hg to 0.29 [0.01] mL/mm Hg in placebo group, P = .004), and reduced central (7.6 [0.4] m/s to 5.9 [0.3] m/s in perindopril group, P < .001 vs placebo) and peripheral (10.9 [0.4] m/s to 8.7 [0.4] m/s in perindopril group, P < .001 vs placebo) pulse wave velocities. In addition, perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (P<.01 to P < .001 for all comparisons between groups). Although perindopril marginally reduced mean arterial pressure (from 81 [2] mm Hg to 80 [1] mm Hg in perindopril group vs 83 [2] mm Hg to 84 [3] mm Hg in placebo group, P = .004), the observed changes in both stiffness and left ventricular outflow tract diameter remained significant when mean arterial pressure was included as a covariate. Transforming growth factor (TGF-), which contributes to aortic degeneration in Marfan syndrome, was reduced by perindopril compared with placebo in both latent (59 [6] ng/mL to 45 [3] ng/mL in perindopril group, P = .01 vs placebo) and active (46 [2] ng/mL to 42 [1] ng/mL in perindopril group, P = .02 vs placebo) forms. Conclusions  Perindopril reduced both aortic stiffness and aortic root diameter in patients with Marfan syndrome taking standard -blocker therapy, possibly through attenuation of TGF- signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome. Trial Registration  clinicaltrials.gov Identifier: NCT00485368      

Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation

Context  Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis. Objective  To assess the association between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease. Design, Setting, and Patients  An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n = 3165) or DES (n = 1501). Landmark analyses were performed among patients who were event-free (no death, myocardial infarction [MI], or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. Main Outcome Measures  Death, nonfatal MI, and the composite of death or MI at 24-month follow-up. Results  Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, –3.3%; 95% CI, –6.3% to –0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, –4.1%; 95% CI, –7.6% to –0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, –0.7%; 95% CI, –2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, –0.5%; 95% CI, –3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, –3.5%; 95% CI, –5.9% to –1.1%; P = .004) and death or MI (0% vs 4.5%; difference, –4.5%; 95% CI, –7.1% to –1.9%; P<.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, –1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, –1.6% to 3.6%; P = .44). Conclusions  The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial.