Javier Mariani

Omega-3 Fatty Acids for the Prevention of Recurrent Symptomatic Atrial Fibrillation: Results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) Trial

OBJECTIVES The aim of this study was to evaluate the efficacy of polyunsaturated fatty acids (n-3 PUFA) for the prevention of recurrent atrial fibrillation (AF) in patients with normal sinus rhythm. BACKGROUND Current pharmacological treatments to limit recurrent AF in patients with previous AF have limited efficacy and high rates of adverse events. Results of trials that tested the efficacy of n-3 PUFA provided heterogeneous results. METHODS This was a prospective, randomized, double-blind, placebo-controlled, multicenter trial involving 586 outpatient participants with confirmed symptomatic paroxysmal AF that required cardioversion (n = 428), at least 2 episodes of AF in the 6 months before randomization (n = 55), or both (103). Patients were randomly allocated to n-3 PUFA (1 g/day) or placebo for 12 months. The primary endpoint was symptomatic recurrence of AF. RESULTS There were no significant differences between patients allocated to placebo and those who received n-3 PUFA for the main outcome. At 12 months, 56 of 297 participants (18.9%) in the placebo group and 69 of 289 participants (24.0%) in the n-3 PUFA group had a recurrent symptomatic AF (hazard ratio: 1.28, 95% confidence interval: 0.90 to 1.83, p = 0.17). There was no difference between treatment with placebo and n-3 PUFA for any of the other pre-specified endpoints, including the composite of all-cause mortality, nonfatal stroke, nonfatal acute myocardial infarction, systemic embolism, heart failure development, or severe bleeding that occurred in 20 (6.7%) and 16 (5.5%) of patients randomized to placebo or n-3 PUFA, respectively (hazard ratio: 0.86, 95% confidence interval: 0.44 to 1.66, p = 0.65). CONCLUSIONS Pharmacological supplementation with 1 g of n-3 PUFA for 1 year did not reduce recurrent AF. (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation [FORWARD]; NCT00597220).

N-3 Polyunsaturated Fatty Acids to Prevent Atrial Fibrillation: Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Previous studies have suggested that n‐3 polyunsaturated fatty acids (n‐3 PUFAs) have antiarrhythmic effects on atrial fibrillation (AF). We aimed to assess the effects of therapy with n‐3 PUFAs on the incidence of recurrent AF and on postoperative AF. Methods and Results Electronic searches were conducted in Web of Science, Medline, Biological Abstracts, Journal Citation Reports, and the Cochrane Central Register of Controlled Trials databases. In addition, data from the recently completed FORωARD and OPERA trials were included. We included randomized controlled trials comparing treatment with n‐3 PUFAs versus control to (1) prevent recurrent AF in patients who underwent reversion of AF or (2) prevent incident postoperative AF after cardiac surgery. Of identified studies, 12.9% (16 of 124) were included, providing data on 4677 patients. Eight studies (1990 patients) evaluated n‐3 PUFA effects on AF recurrence among patients with reverted AF and 8 trials (2687 patients) on postoperative AF. Pooled risk ratios through random‐effects models showed no significant effects on AF recurrence (RR, 0.95; 95% CI, 0.79 to 1.13; I2, 72%) or on postoperative AF (0.86; 95% CI, 0.71 to 1.04; I2, 53.1%). A funnel plot suggested publication bias among postoperative trials but not among persistent AF trials. Meta‐regression analysis did not find any relationship between doses and effects (P=0.887 and 0.833 for recurrent and postoperative AF, respectively). Conclusions Published clinical trials do not support n‐3 PUFAs as agents aimed at preventing either postoperative or recurrent AF. Clinical Trial Registration URL: http://www.crd.york.ac.uk/PROSPERO. Unique Identifier: CRD42012002199.

Clinical ResearchHeart Rhythm Disorders in Heart FailureOmega-3 Fatty Acids for the Prevention of Recurrent Symptomatic Atrial Fibrillation: Results of the FORWARD (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation) Trial

OBJECTIVES The aim of this study was to evaluate the efficacy of polyunsaturated fatty acids (n-3 PUFA) for the prevention of recurrent atrial fibrillation (AF) in patients with normal sinus rhythm. BACKGROUND Current pharmacological treatments to limit recurrent AF in patients with previous AF have limited efficacy and high rates of adverse events. Results of trials that tested the efficacy of n-3 PUFA provided heterogeneous results. METHODS This was a prospective, randomized, double-blind, placebo-controlled, multicenter trial involving 586 outpatient participants with confirmed symptomatic paroxysmal AF that required cardioversion (n = 428), at least 2 episodes of AF in the 6 months before randomization (n = 55), or both (103). Patients were randomly allocated to n-3 PUFA (1 g/day) or placebo for 12 months. The primary endpoint was symptomatic recurrence of AF. RESULTS There were no significant differences between patients allocated to placebo and those who received n-3 PUFA for the main outcome. At 12 months, 56 of 297 participants (18.9%) in the placebo group and 69 of 289 participants (24.0%) in the n-3 PUFA group had a recurrent symptomatic AF (hazard ratio: 1.28, 95% confidence interval: 0.90 to 1.83, p = 0.17). There was no difference between treatment with placebo and n-3 PUFA for any of the other pre-specified endpoints, including the composite of all-cause mortality, nonfatal stroke, nonfatal acute myocardial infarction, systemic embolism, heart failure development, or severe bleeding that occurred in 20 (6.7%) and 16 (5.5%) of patients randomized to placebo or n-3 PUFA, respectively (hazard ratio: 0.86, 95% confidence interval: 0.44 to 1.66, p = 0.65). CONCLUSIONS Pharmacological supplementation with 1 g of n-3 PUFA for 1 year did not reduce recurrent AF. (Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial Fibrillation [FORWARD]; NCT00597220).

Previous prescription of β-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis*

Objectives: Results from basic science and narrative reviews suggest a potential role of &bgr;-blockers in patients with sepsis. Although the hypothesis is physiologically appealing, it could be seen as clinically counterintuitive. We sought to assess whether patients previously prescribed chronic &bgr;-blocker therapy had a different mortality rate than those who did not receive treatment. Setting: Record linkage of administrative databases of Italian patients hospitalized for sepsis during years 2003–2008 were identified and followed up for all-cause mortality at 28 days. Interventions: None. Measurements and Main Results: We identified 9,465 patients aged ≥40 yrs who were hospitalized in critical care units for sepsis. Of these, 1,061 patients were on chronic prescription with &bgr;-blockers and 8404 were not previously treated. Despite a higher risk profile, patients previously prescribed with &bgr;-blockers had lower mortality at 28 days (188/1061 [17.7%]) than those previously untreated (1857/8404 [22.1%]) (odds ratio 0.78; 95% confidence interval 0.66–0.93; p = .005 for unadjusted analysis, and odds ratio 0.81; 95% confidence interval 0.68–0.97; p = .025 for adjusted analyses). Sensitivity and pair-matched results confirm the primary findings. Conclusions: As far as we are aware, this pharmacoepidemiologic assessment is the largest to examine the potential association of previous &bgr;-blocker prescription and mortality in patients with sepsis. Chronic prescription of &bgr;-blockers may confer a survival advantage to patients who subsequently develop sepsis with organ dysfunction and who are admitted to an intensive care unit. Prospective randomized clinical trials should formally test this hypothesis.

Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema: A Meta-Analysis of Randomized Controlled Trials

BACKGROUND The evidence of individual studies in acute cardiogenic pulmonary edema (ACPE) supporting noninvasive ventilation (NIV) is still inconclusive, particularly regarding noninvasive positive pressure ventilation (NIPPV). METHODS We carried out a meta-analysis. We searched in the Embase, Medline, Cinahl, Dare, Coch, Central, and CNKI databases and congress abstracts for trials comparing continuous positive airway pressure (CPAP) or NIPPV with standard therapy (ST). To assess treatment effects, we carried out direct comparison using a random effects model and adjusted indirect comparison. RESULTS At total of 34 studies (3,041 patients) were included. In direct comparisons, both CPAP and NIPPV reduced the risk of death (relative risk [RR] 0.64, 95% CI 0.44-0.93; RR 0.80, 95% CI 0.58-1.10; respectively) compared with ST, although only CPAP had a significant effect. There were no significant differences between NIPPV and CPAP. Pooled results of direct and adjusted indirect comparisons showed that compared with ST, both CPAP and NIPPV significantly reduced mortality (RR 0.63, 95% CI 0.44-0.89; RR 0.73, 95% CI 0.55-0.97; respectively). CONCLUSIONS Our findings suggest that among ACPE patients, NIV delivered through either NIPPV or CPAP reduced mortality.

Exploratory Analysis on the Use of Statins with or without n-3 PUFA and Major Events in Patients Discharged for Acute Myocardial Infarction: An Observational Retrospective Study

Background Combined treatment (CT) with statins and polyunsaturated fatty acids (n-3 PUFA) resulted in a reduction of death and major cardiovascular events when administered after a myocardial infarction (MI). However, recent data suggests that CT may be ineffective because patients are currently treated aggressively and the risk may not be further decreased. We aimed to study the prevalence and the results on major outcomes with CT among patients discharged with a MI in Italy. Methodology/Principal findings Retrospective cohort study that used linked hospital discharge, prescription databases and vital statistics containing information on 14,704 patients who were discharged for MI between 1/2003 and 12/2003 in 117 hospitals in Italy. All analyses were time-dependent and adjusted for major confounders. Sensibility and paired matched analysis were conducted to further verify main results. A total of 11,532 (78.4%) filled a prescription for a statin. Of these, 4302 (37.3%) were on CT. There were 45,528 patients/years of follow-up. As compared with statins alone, CT was associated with an adjusted higher survival rate (HR = 0.59 [0.52–0.66], p<0.001), survival free of atrial fibrillation (HR = 0.78 [0.71–0.86], p<0.001) and survival free of new heart failure development (HR = 0.81 [0.74–0.88], p<0.001), but not with re-infarction (HR = 0.94 [0.86–1.02], p<0.127). Clinically this means that between 2 to 3 fewer events for each 100 patients/year were obtained in the group under CT. Conclusions/Significance Among a representative sample of patients discharged with MI in Italy, we observed clinically significant synergism between the effects of statins and n-3 PUFA for most cardiovascular outcomes, including all cause mortality.

Statins but Not Aspirin Reduce Thrombotic Risk Assessed by Thrombin Generation in Diabetic Patients without Cardiovascular Events: The RATIONAL Trial

Background The systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events. Methodology/Principal Findings Prospective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent. Conclusions/Significance While waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG. Trial Registration ClinicalTrials.gov NCT00793754

Temporal trends of the gaps in post-myocardial infarction secondary prevention strategies of co-morbid and elderly populations vs. younger counterparts: an analysis of three successive cohorts between 2003 and 2008

Aims Epidemiological studies reported two contrasting trends: on one hand, a significant improvement in the use of evidence-based treatments of patients discharged with a myocardial infarction (MI). On the other hand, the increasing number of elderly and co-morbid patients who are usually less treated. The aim of this study is to examine whether improvements in the treatment of MI are homogeneously distributed throughout all subgroups of patients. Methods and results Based on record linkage of administrative registers, 21 423 patients discharged with MI in three different periods (2003, 2005, and 2007), were identified and followed up for major clinical events up to 1 year. Using as a reference temporal category those patients discharged in 2003 (odds ratios, 95% confidence intervals) and as a demographic category male patients aged ≤75 years (1.00), the study identified: in-hospital mortality significantly decreased in all periods and in all groups of patients; out-of-hospital mortality decreased only in younger patients and not in older patients; prescription of evidence-based treatments increased in all periods for all patients; however, the magnitude of improvement was mostly concentrated in younger patients. Conclusion Although there was a mean improvement in the treatment and outcome of patients discharged from an MI, most of these benefits were strongly concentrated in younger, healthier patients. Old and co-morbid populations-although representing a substantial proportion of the burden of disease-received significant less attention and barely improved their survival.

Circulating cardiac biomarkers and postoperative atrial fibrillation in the OPERA trial

Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients.

Multivessel versus Single Vessel Angioplasty in Non-ST Elevation Acute Coronary Syndromes: A Systematic Review and Metaanalysis

Background Multivessel disease is common in acute coronary syndrome patients. However, if multivessel percutaneous coronary intervention is superior to culprit-vessel angioplasty has not been systematically addressed. Methods A metaanalysis was conducted including studies that compared multivessel angioplasty with culprit-vessel angioplasty among non-ST elevation ACS patients. Since all studies were observational adjusted estimates of effects were used. Pooled estimates of effects were computed using the generic inverse of variance with a random effects model. Results Twelve studies were included (n = 117,685). Median age was 64.1 years, most patients were male, 29.3% were diabetic and 36,9% had previous myocardial infarction. Median follow-up was 12 months. There were no significant differences in mortality risk (HR 0.79; 95% CI 0.58 to 1.09; I2 67.9%), with moderate inconsistency. Also, there were no significant differences in the risk of death or MI (HR 0.90; 95% CI 0.69 to 1.17; I2 62.3%), revascularization (HR 0.76; 95% CI 0.55 to 1.05; I2 49.9%) or in the combined incidence of death, myocardial infarction or revascularization (HR 0.83; 95% CI 0.66 to 1.03; I2 70.8%). All analyses exhibited a moderate degree of inconsistency. Subgroup analyses by design reduced the inconsistency of the analyses on death or myocardial infarction, revascularization and death, myocardial infarction or revascularization. There was evidence of publication bias (Egger’s test p = 0.097). Conclusion Routine multivessel angioplasty in non-ST elevation acute coronary syndrome patients with multivessel disease was not superior to culprit-vessel angioplasty. Randomized controlled trials comparing safety and effectiveness of both strategies in this setting are needed.