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Nuesch E.,University of Bern | Trelle S.,University of Bern | Reichenbach S.,University of Bern | Rutjes A.W.S.,University of Bern | And 5 more authors.
BMJ (Online) | Year: 2010

Objective: To examine the presence and extent of small study effects in clinical osteoarthritis research. Design: Meta-epidemiological study. Data sources: 13 meta-analyses including 153 randomised trials (41 605 patients) that compared therapeutic interventions with placebo or nonintervention control in patients with osteoarthritis of the hip or knee and used patients' reported pain as an outcome. Methods: We compared estimated benefits of treatment between large trials (at least 100 patients per arm) and small trials, explored funnel plots supplemented with lines of predicted effects and contours of significance, and used three approaches to estimate treatment effects: meta-analyses including all trials irrespective of sample size, meta-analyses restricted to large trials, and treatment effects predicted for large trials. Results: On average, treatment effects were more beneficial in small than in large trials (difference in effect sizes -0.21, 95% confidence interval -0.34 to -0.08, P=0.001). Depending on criteria used, six to eight funnel plots indicated small study effects. In six of 13 meta-analyses, the overall pooled estimate suggested a clinically relevant, significant benefit of treatment, whereas analyses restricted to large trials and predicted effects in large trials yielded smaller non-significant estimates. Conclusions: Small study effects can often distort results of meta-analyses. The influence of small trials on estimated treatment effects should be routinely assessed. Source

Di Nisio M.,University of Chieti Pescara | Van Sluis G.L.,University of Amsterdam | Bossuyt P.M.M.,University of Amsterdam | Buller H.R.,University of Amsterdam | And 3 more authors.
Journal of Thrombosis and Haemostasis | Year: 2010

Background: The best available test for the diagnosis of upper extremity deep venous thrombosis (UEDVT) is contrast venography. The aim of this systematic review was to assess whether the diagnostic accuracy of other tests for clinically suspected UEDVT is high enough to justify their use in clinical practise and to evaluate if any test can replace venography. Methods: MEDLINE and EMBASE databases were searched from inception to June 2009. Two reviewers independently evaluated study eligibility, extracted data, and assessed study quality. Results: We identified 17 papers, reporting on 793 patients. Overall, the methodological quality was poor, sample sizes were small, and large between-study differences were observed in spectrum and design. The summary estimates of sensitivity (95% confidence interval) were 97% (90-100%) for compression ultrasonography, 84% (72-97%) for Doppler ultrasonography, 91% (85-97%) for Doppler ultrasonography with compression, and 85% (72-99%) for phleboreography. The corresponding summary estimates of specificity were, respectively, 96% (87-100%), 94% (86-100%), 93% (80-100%), and 87% (71-100%). Clinical findings, a clinical score, D-dimer, magnetic resonance imaging, rheography and plethysmography were evaluated in one study each, involving a median number of 46 patients (range 21-214). Sensitivity and specificity ranged from 0% to 100% and from 14% to 100%. Conclusions: Methodological limitations, large between-study differences and small sample sizes limit the evidence of tests for clinically suspected UEDVT. Compression ultrasonography may be an acceptable alternative to venography. The addition of (color) Doppler does not seem to improve the accuracy. Adequately designed studies are warranted to confirm these findings. © 2010 International Society on Thrombosis and Haemostasis. Source

Savarese G.,University of Naples Federico II | Dei Cas A.,University of Parma | Rosano G.,Istituto di Ricovero e Cura rattere Scientifico San Raffaele Pisana | D'Amore C.,University of Naples Federico II | And 6 more authors.
International Journal of Cardiology | Year: 2014

Background The association between renal dysfunction and risk of cardiovascular (CV) events and mortality has been reported in several studies. However, it is unclear whether reduction in urinary albumin excretion (UAE) is associated with reduced risk of clinical events. Therefore, we sought to investigate, in a meta-regression analysis of randomized studies enrolling hypertensive and/or diabetic patients, whether changes in UAE are associated with changes in CV outcomes and all-cause mortality. Methods MEDLINE, ISI Web of Science, Cochrane Database and Scopus were searched for randomized trials enrolling more than 200 diabetic and/or hypertensive patients, reporting UAE at baseline and at end of follow-up and CV events [CV death, myocardial infarction (MI), and stroke], as well all-cause mortality. Results Thirty-two trials enrolling 80,812 participants were included in analyses. Meta-regression analysis showed that each 10% reduction of UAE was significantly associated with 13% reduction of MI (Regression Coefficient [RC]:0.0055; 95% Confidence Interval [CI]:0.0014 to 0.0095; p = 0.010), with 29% reduction of stroke (RC:0.0124; CI:0.0030 to 0.0218; p = 0.013) and with 14% reduction of the composite outcome (CV death, MI, stroke)(RC:0.0059; CI:0.0027 to 0.0090; p = 0.001), whereas not significantly associated with all-cause (RC:0.0028; CI:- 0.0047 to 0.0103; p = 0.486) and CV mortality (RC:0.0028; CI:- 0.0047 to 0.0103; p = 0.447). Results were mostly confirmed by sensitivity analysis. No heterogeneity or publication bias was detected. Conclusions Reduction in UAE is associated with reduced risk of MI and stroke in diabetic and/or hypertensive patients. These findings suggest that UAE changes may represent a valuable intermediate end-point for CV risk evaluation in clinical practice. © 2014 Elsevier Ireland Ltd. Source

Mozaffarian D.,Brigham and Womens Hospital | Mozaffarian D.,Harvard University | Marchioli R.,Consorzio Mario Negri Sud | Marchioli R.,Laboratory of Clinical Epidemiology of Cardiovascular Disease | And 11 more authors.
JAMA - Journal of the American Medical Association | Year: 2012

Context: Postoperative atrial fibrillation or flutter (AF) is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-polyunsaturated fatty acids (PUFAs) reduce postoperative AF, with mixed results. Objective: To determine whether perioperative n-3-PUFA supplementation reduces postoperative AF. Design, Setting, and Patients: The Omega-3 Fatty Acids for Prevention of Postoperative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial. A total of 1516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment. Intervention: Patients were randomized to receive fish oil (1-g capsules containing ≥840 mg n-3-PUFAs as ethyl esters) or placebo, with preoperative loading of 10 g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. Main Outcome Measure: Occurrence of postoperative AF lasting longer than 30 seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse cardiovascular events, 30-day mortality, bleeding, and other adverse events. Results: At enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, 0.96 [95% CI, 0.77-1.20]; P=.74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P=.70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; ≥3 episodes: 18 [2.4%] vs 21 [2.8%]) (P=.73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events. Conclusion: In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF. Trial Registration: clinicaltrials.gov Identifier: NCT00970489. ©2012 American Medical Association. All rights reserved. Source

Masson S.,Istituto di Ricerche Farmacologiche Mario Negri | Marchioli R.,Laboratory of Clinical Epidemiology of Cardiovascular Disease | Mozaffarian D.,Brigham and Womens Hospital | Bernasconi R.,Istituto di Ricerche Farmacologiche Mario Negri | And 12 more authors.
American Heart Journal | Year: 2013

Treatment with long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) can improve clinical outcomes in patients with heart failure (HF). Circulating levels of n-3 PUFA, an objective estimation of exposure, have never been measured in a large cohort of patients with HF. Methods: We measured n-3 PUFA in plasma phospholipids at baseline and after 3 months in 1,203 patients with chronic HF enrolled in the GISSI-Heart Failure trial and randomized to n-3 PUFA 1 g/daily or placebo. N-3 PUFA levels were related to clinical characteristics, pharmacologic treatments, dietary habits, circulating biomarkers, and mortality. Results: Baseline n-3 PUFA (5.1 ± 1.8 mol%) was associated with dietary fish intake, with an average difference of 43% between patients with the lowest and highest consumptions (P <.0001). Baseline eicosapentaenoic acid (EPA) but not docosahexaenoic acid (DHA) was inversely related to C-reactive protein, pentraxin-3, adiponectin, natriuretic peptide, and troponin levels. Three-month treatment with n-3 PUFA raised their levels by 43%, independently of dietary fish consumption; increases in EPA levels were associated with decreased pentraxin-3. Low baseline levels of EPA but not DHA were no longer related to higher mortality after the addition of circulating biomarkers to multivariable models. Conclusion: Before supplementation, circulating n-3 PUFA levels in patients with chronic HF mainly depend on dietary fish consumption and are inversely related to inflammatory markers and disease severity. Three-month treatment with n-3 PUFA markedly enriched circulating EPA and DHA, independently of fish intake, and lowered pentraxin-3. Low EPA levels are inversely related to total mortality in patients with chronic HF. © 2013 Mosby, Inc. All rights reserved. Source

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