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Mozaffarian D.,Brigham and Women's 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.


Marfisi R.,Laboratory of Clinical Epidemiology of Cardiovascular Disease | Marchioli R.,Laboratory of Clinical Epidemiology of Cardiovascular Disease
Internal and Emergency Medicine | Year: 2012

In polycythemia vera, gender has recently been shown to influence the JAK2V617F allele burden, but its effect on the disease phenotype is unknown. This issue was investigated using the database of the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study. The ECLAP Study recruited 1,638 polycythemic subjects and followed for 2. 7 ± 1. 3 years. At study entry, men, compared to women, had a higher prevalence of myocardial infarction (11. 3 vs. 5. 8%; P < 0. 0001) and peripheral arterial disease (6. 1 vs. 2. 9%; P < 0. 05) while a history of venous thrombosis was more common in women (11. 4 vs. 7. 9%, P = 0. 016). Among 234 venous thrombosis, there were 39 splanchnic vein thromboses (33 extra-hepatic portal vein thromboses and 6 Budd-Chiari syndromes). Most of these events occurred as an early disease presentation in young female subjects. Women, compared to men, had higher platelet counts (average value 430 ± 213 vs. 375 ± 201 × 109/L; P < 0. 0001) and lower hematocrits (0. 46 ± 0. 06 vs. 0. 48 ± 0. 06 l/l; P < 0. 0001). Cholesterol plasma level, available in 995 subjects (61%), was lower in male patients (180. 8 ± 43. 1vs. 196 ± 46. 6 mg/dl; P < 0. 0001). During follow-up there were 205 major thromboses confirming an high incidence of myocardial infarction in men although not statistically significant (1. 2 vs. 0. 6 cases per 100 person-years; P > 0. 05). These data show several gender-related differences both in the thrombotic diathesis and in the prevalence of vascular risk factors of PV patients. © 2011 SIMI.


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.


Savarese G.,University of Naples Federico II | Dei Cas A.,University of Parma | Rosano G.,Instituto Of Ricovero E Cura A Carattere 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.


PubMed | Cantonal Hospital of Baden, University of Parma, University of Naples Federico II, Laboratory of Clinical Epidemiology of Cardiovascular Disease and Instituto Of Ricovero E Cura A Carattere Scientifico San Raffaele Pisana
Type: Journal Article | Journal: International journal of cardiology | Year: 2014

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.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.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.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.


PubMed | University of New South Wales, Brown University, Cardiac Surgery, L.E.S.S. and 10 more.
Type: Clinical Trial | Journal: Journal of the American Heart Association | Year: 2015

Animal study results point to oxidative stress as a key mechanism triggering postoperative atrial fibrillation (PoAF), yet the extent to which specific biomarkers of oxidative stress might relate to PoAF risk in humans remains speculative.We assessed the association of validated, fatty acid-derived oxidative stress biomarkers (F2-isoprostanes, isofurans, and F3-isoprostanes) in plasma and urine, with incident PoAF among 551 cardiac surgery patients. Biomarkers were measured at enrollment, the end of surgery, and postoperative day 2. PoAF lasting 30 seconds was confirmed with rhythm strip or electrocardiography and centrally adjudicated. Outcomes were assessed until hospital discharge or postoperative day 10, whichever occurred first. Urine level of each oxidative stress biomarker rose at the end of surgery (2- to 3-fold over baseline, P<0.001) and subsequently declined to concentrations comparable to baseline by postoperative day 2. In contrast, plasma concentrations remained relatively stable throughout the perioperative course. Urine F2-isoprostanes and isofurans at the end of surgery were 20% and 50% higher in subjects who developed PoAF (P0.009). While baseline biomarker levels did not associate significantly with PoAF, end of surgery and postoperative day 2 isoprostanes and isofurans demonstrated relatively linear associations with PoAF. For example, the end of surgery extreme quartile multivariate adjusted OR (95% CI) for urine isofurans and F3-isoprostanes were 1.95 (1.05 to 3.62; P for trend=0.01) and 2.10 (1.04 to 2.25, P for trend=0.04), respectively. The associations of biomarkers with PoAF varied little by demographics, surgery type, and medication use (P0.29 for each).These novel results add to accumulating evidence supporting the likely key pathogenic role of elevated oxidative stress in PoAF.URL: Clinicaltrials.gov Unique identifier: NCT00970489.


Barbui T.,Ospedali Riuniti di Bergamo | Carobbio A.,Ospedali Riuniti di Bergamo | Finazzi G.,Ospedali Riuniti di Bergamo | Vannucchi A.M.,University of Florence | And 12 more authors.
Haematologica | Year: 2011

We tested the hypothesis that levels of pentraxin high sensitivity C-reactive protein and pentraxin 3 might be correlated with cardiovascular complications in patients with essential thrombocythemia and polycythemia vera. High sensitivity C-reactive protein and pentraxin 3 were measured in 244 consecutive essential thrombocythemia and polycythemia vera patients in whom, after a median follow up of 5.3 years (range 0-24), 68 cardiovascular events were diagnosed. The highest C-reactive protein tertile was compared with the lowest (>3 vs. <1 mg/L) and correlated with age (P=0.001), phenotype (polycythemia vera vs. essential thrombocythemia, P=0.006), cardiovascular risk factors (P=0.012) and JAK2V617F allele burden greater than 50% (P=0.003). Major thrombosis rate was higher in the highest C-reactive protein tertile (P=0.01) and lower at the highest pentraxin 3 levels (P=0.045). These associations remained significant in multivariate analyses and indicate that blood levels of high sensitivity C-reactive protein and petraxin 3 independently and in opposite ways modulate the intrinsic risk of cardiovascular events in patients with myeloproliferative disorders & copy 2011 Ferrata Storti Foundation.


Marchioli R.,Laboratory of Clinical Epidemiology of Cardiovascular Disease | Marchioli R.,Italian Society of Cardiology Research Center | Levantesi G.,Laboratory of Clinical Epidemiology of Cardiovascular Disease | Levantesi G.,S Pio Hospital Vasto
Frontiers in Physiology | Year: 2012

After the first reports about a protective effect on coronary heart disease (CHD) published more than 40 years ago, wide interest in the therapeutic use of n-3 polyunsaturated fatty acids (n-3 PUFA) aroused. Since then, many studies and meta-analyses have reported a significantly reduced risk of CHD and CV death due to fish and n-3 PUFA intake. Some of the overviews reported a significant reduction of risk of sudden cardiac death, all-cause death, and nonfatal CV events. On the other side, recent clinical trials had mixed findings, raising concern about the consistency of the evidence on n-3 PUFA. We critically reviewed recent large clinical trials reporting data on the antiarrhythmic effects of n-3 PUFA in different clinical settings, i.e., patients with CHD, heart failure, with implantable cardioverter defibrillator, and at risk of atrial fibrillation, in order to summarize the results which are available up to date and possibly give "substantiated" fuel to the debate on the conflicting results of n-3 PUFA. © 2012 Marchioli and Levantesi.


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.

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