Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial

Context  Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients. Objective  To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer. Design, Setting, and Patients  Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death. Intervention  Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment. Main Outcome Measures  Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer. Results  Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, P.01 for both groups; QOL, P<.001 for both groups), with a larger decrease in pain for the NCPB group (P = .005). From repeated measures analysis, pain was also lower for NCPB over time (P = .01). However, opioid consumption (P = .93), frequency of opioid adverse effects (all P>.10), and QOL (P = .46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of =" BORDER="0">5/10) vs opioid-only patients (14% vs 40%, P = .005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P = .26, proportional hazards regression). Conclusion  Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival.      

C-reactive protein and the risk of incident colorectal cancer

Context  Inflammation may play a role in the pathogenesis of colorectal cancer; however, epidemiological evidence supporting this hypothesis in average-risk persons is sparse. Objective  To determine the risk of incident colon and rectal cancer associated with elevated baseline plasma concentrations of C-reactive protein (CRP). Design, Setting, and Participants  Prospective, nested case-control study of a cohort of 22 887 adults (>18 years and Washington County, Maryland, residents) enrolled between May and October 1989 and followed up through December 2000. A total of 172 colorectal cancer cases were identified through linkage with the Washington County and Maryland State Cancer registries. Up to 2 controls (n = 342) were selected from the cohort for each case and matched by age, sex, race, and date of blood draw. Main Outcome Measure  Odds ratio (OR) of incident colon and rectal cancer. Results  Plasma CRP concentrations were higher among all colorectal cases combined than controls (median CRP, 2.44 vs 1.94 mg/L; P = .01). The highest concentration was found in persons who subsequently developed colon cancer vs matched controls (median CRP, 2.69 vs 1.97 mg/L; P<.001). Among rectal cancer cases, CRP concentrations were not significantly different from controls (median CRP, 1.79 vs 1.81 mg/L; P = .32). The risk of colon cancer was higher in persons in the highest vs lowest quartile of CRP (OR, 2.55; 95% confidence interval [CI], 1.34-4.88; P for trend = .002). In nonsmokers, the corresponding association was stronger (OR, 3.51; 95% CI, 1.64-7.51; P for trend<.001). A 1-SD increase in log CRP (1.02 mg/L) was associated with an increased risk of colon cancer after adjusting for potential confounders and excluding cases occurring within 2 years of baseline (OR, 1.35; 95% CI, 1.05-1.74) or excluding those with late-stage colon cancer at the time of diagnosis (OR, 1.38; 95% CI, 0.99-1.91). Conclusions  Plasma CRP concentrations are elevated among persons who subsequently develop colon cancer. These data support the hypothesis that inflammation is a risk factor for the development of colon cancer in average-risk individuals.      

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      

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.      

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.      

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.      

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 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 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      

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.