A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Cancer in chronic heart failure patients in the GISSI-HF trial.

BACKGROUND: Cancer complicating heart failure (HF) is an emerging issue. We investigated it in the GISSI-HF trial, which uniquely included patients with malignancies if deemed likely to allow follow-up. METHODS AND RESULTS: At enrolment, 256 of 6913 participants in GISSI-HF (3.7%) had a tumour diagnosis, which was malignant (cancer) in 145 (2.1%). Patients with cancer were older and more often former smokers, had lower body mass index, lower left ventricular ejection fraction (LVEF), less implanted devices, lower glucose and haemoglobin and higher uric acid levels than those without cancer. During a median 4-year follow-up, cardiovascular (CV), non-CV non-cancer and cancer death occurred in 1477, 272 and 220 subjects (75%, 13.8% and 11.2% of total mortality, respectively). Cancer at trial entry portended an increased risk of all-cause mortality after accounting for age and confounders (HR 1.33, 95%CI 1.02-1.73), which was attributable to cancer-specific mortality. Among the 6657 patients without any tumour at enrolment, 1879 subsequently died. CV, non-CV non-cancer and cancer causes accounted for 1422 (75.7%), 261 (13.9%) and 196 (10.4%) of these deaths, respectively, median time to specific death being 22, 25 and 30 months (P < .0001). Patients facing cancer vs CV death had lower NYHA class, slower heart rate, higher blood pressure, higher LVEF, shorter HF history, less diuretic use, lower creatinine and uric acid and higher haemoglobin and cholesterol. CONCLUSIONS: Even when considered not aggressive, concomitant cancer worsens HF prognosis. The inverse relationship between HF severity and cancer death in the absence of prior tumour warrants further study.

Modes of death and prognostic outliers in chronic heart failure.

BACKGROUND: The impact of incident sudden cardiac death (SCD) on the predictive accuracy of prognostic risk scores for patients with chronic heart failure (HF) has rarely been examined. We assessed the relationship between estimated probability of death and modes of death in this population, as well as the predictors of death and survival in prognostic outliers. METHODS AND RESULTS: The MAGGIC 3-year probability of death was estimated in 6,859 participants of the GISSI-HF trial (mean age 67±11 years, 78% men, 91% with ejection fraction <40%, mean follow-up 3.5±1.3 years, observed mortality 28.4%). The incidence of SCD progressively decreased with increased probability of death, and occurred in 52.5% of patients estimated at low-risk (N = 61 with probability <14%) vs. in 23.5% of the high-risk ones (N = 375 with probability >56%, P < .0001). On the contrary, death from worsening HF was significantly more frequent in the latter group (19.7% vs. 46.1%, P < .0001). The overall predictive accuracy of the MAGGIC model improved after excluding deaths from SCD (AUC from 0.731 to 0.760, P = .0034). Among patients estimated at low-risk (N = 61 dead, 743 alive), independent predictors of death were older age, longer history of HF, higher serum uric acid and chronic obstructive pulmonary disease. The only predictor of survival in patients estimated at high-risk (N = 210 alive, 375 dead) was higher systolic blood pressure. CONCLUSIONS: The MAGGIC risk score demonstrated its scarce ability to capture SCD, particularly in chronic HF patients estimated at low risk of death. Newer and better prognostic tools in the evolving horizon of HF are needed.

Fish Oil Supplementation Does Not Affect Cognitive Outcomes in Cardiac Surgery Patients in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial.

Background: Cognitive decline has been reported following cardiac surgery, leading to great interest in interventions to minimize its occurrence. Long-chain n-3 (ω-3) polyunsaturated fatty acids (PUFAs) have been associated with less cognitive decline in observational studies, yet no trials have tested the effects of n-3 PUFAs on cognitive decline after surgery. Objective: We sought to determine whether perioperative n-3 PUFA supplementation reduces postoperative cognitive decline in patients postcardiac surgery. Methods: The study comprised a randomized, double-blind, placebo-controlled, multicenter, clinical trial conducted on cardiac surgery recipients at 9 tertiary care medical centers across the United States. Patients were randomly assigned to receive fish oil (1-g capsules containing ≥840 mg n-3 PUFAs as ethyl esters) or placebo, with preoperative loading of 8-10 g over 2-5 d followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. Global cognition was assessed using in-person testing over 30 d with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) (primary outcome), Mini-Mental State Exam (secondary outcome), and Trails A and B (secondary outcome) tests. All end points were prespecified. Statistical methods were employed, including descriptive statistics, logistic regression, and various sensitivity analyses. Results: A total of 320 US patients were enrolled in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Cognitive Trial (OCT), a substudy of OPERA. The median age was 62 y (IQR 53, 70 y). No differences in global cognition were observed between placebo and fish oil groups at day 30 (P = 0.32) for the primary outcome, a composite neuropsychological RBANS score. The population demonstrated resolution of initial 4-d cognitive decline back to baseline function by 30 d on the RBANS. Conclusion: Perioperative supplementation with n-3 PUFAs in cardiac surgical patients did not influence cognition ≤30 d after discharge. Modern anesthetic, surgical, and postoperative care may be mitigating previously observed long-term declines in cognitive function following cardiac surgery. This trial was registered at clinicaltrials.gov as NCT00970489.

Prognostic effects of rosuvastatin in patients with co-existing chronic obstructive pulmonary disease and chronic heart failure: A sub-analysis of GISSI-HF trial.

OBJECTIVES: Rising evidences showed a possible protective role of statins in chronic obstructive pulmonary disease (COPD). We aimed to evaluate in a post-hoc analysis of the GISSI-HF trial the prognostic effect of the use of rosuvastatin in patients with co-existing COPD and HF, assuming that the anti-inflammatory properties of these drugs may imply a potential beneficial effect in these associated chronic inflammatory conditions. METHODS: We analyzed patients with chronic HF and history of COPD deriving from the GISSI-HF study. Of all 4574 patients eligible to statin, 1060 ambulatory patients with HF and concomitant COPD were enrolled and randomly assigned to rosuvastatin 10 mg daily (538 patients) or placebo (522 patients). The primary end-point was to compare all cause death rate in patients randomized to rosuvastatin or placebo. Further, we assessed the effects of rosuvastatin (10 mg daily) on cardiovascular (CV) death, non-CV death and hospital admissions. Median follow-up was 3.9 years with an interquartile range (IQR) of 3.0-4.4. RESULTS: During the follow-up 438 (41.3%) patients died, 304 (28.6%) for CV death and 687 (64.8%) had at least one hospitalization. The two patient groups had similar outcome, irrespective of randomization, in terms of all-cause mortality (log-rank test p = 0.30) CV, non CV-death (p = 0.88 and 0.09 respectively) and all-cause hospitalization (p = 0.82). Cox regression analysis did not show a favorable association between the use of statin and the examined end-points both on unadjusted and adjusted models. CONCLUSIONS: Statin use is not associated with a beneficial effects on all cause, CV, non CV mortality and hospitalization in patients with coexistent chronic HF and history of COPD. ClinicalTrials.gov Identifier: NCT00336336.

Prevalence and Prognostic Impact of Chronic Obstructive Pulmonary Disease in Patients with Chronic Heart Failure: Data from the GISSI-HF Trial.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure (HF). We aimed to assess its prevalence, characterization and long-term prognostic impact in the GISSI-HF population. METHODS: The study randomized 6,975 ambulatory HF patients to either n-3 polyunsaturated fatty acids or placebo. We performed a retrospective analysis of clinical characteristics and outcomes of the 1,533 patients diagnosed with COPD (22%). RESULTS: COPD was associated with a worse clinical presentation and an increased burden of comorbidities. At a median follow-up of 3.9 years, COPD was found to be an independent predictor of both predefined primary study end points, including all-cause mortality (HR 1.28, 95% CI 1.15-1.43, p < 0.0001) and all-cause mortality or hospitalization for cardiovascular reasons (HR 1.19, 95% CI 1.10-1.30, p < 0.0001). Both cardiovascular (HR 1.20, 95% CI 1.05-1.36, p = 0.007) and noncardiovascular mortality (HR 1.56, 95% CI 1.26-1.94, p < 0.0001) were significantly increased in COPD-HF patients, as well as hospitalizations for any reason (HR 1.23, 95% CI 1.14-1.34, p < 0.0001), for cardiovascular reasons (HR 1.16, 95% CI 1.06-1.27, p = 0.002) and for HF (HR 1.27, 95% CI 1.14-1.43, p < 0.0001). CONCLUSIONS: COPD is an independent predictor of mortality and hospitalizations in ambulatory HF patients. Increased awareness and improved management of COPD may reduce the burden of this morbidity to patients with HF.

n-3 fatty acids in patients with multiple cardiovascular risk factors.

BACKGROUND: Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. METHODS: In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. RESULTS: Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. CONCLUSIONS: In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Società Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.).

Cardiovascular events and intensity of treatment in polycythemia vera.

BACKGROUND: Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. METHODS: We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. RESULTS: After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. CONCLUSIONS: In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis.

From 2007 to 2011, 66 patients with primary myelofibrosis or myelofibrosis (MF) preceded by essential thrombocythemia or polycythemia vera were enrolled into a prospective phase 2 clinical trial of reduced-intensity allogeneic hematopoietic stem cell transplantation (AHSCT), Myeloproliferative Disorder Research Consortium 101 trial. The study included patients with sibling donors (n = 32) receiving fludarabine/melphalan (FluMel) as a preparative regimen and patients with unrelated donors (n = 34) receiving conditioning with FluMel plus anti-thymocyte globulin (ATG). Patient characteristics in the 2 cohorts were similar. Engraftment occurred in 97% of siblings and 76% of unrelated transplants, whereas secondary graft failure occurred in 3% and 12%, respectively. With a median follow-up of 25 months for patients alive, the overall survival (OS) was 75% in the sibling group (median not reached) and 32% in the unrelated group (median OS: 6 months, 95% confidence interval [CI]: 3, 25) (hazard ratio 3.9, 95% CI: 1.8,8.9) (P < .001). Nonrelapse mortality was 22% in sibling and 59% in unrelated AHSCT. Survival correlated with type of donor, but not with the degree of histocompatibility match, age, or JAK2(V617F) status. In patients with MF with sibling donors, AHSCT is an effective therapy, whereas AHSCT from unrelated donors with FluMel/ATG conditioning led to a high rate of graft failure and limited survival. This trial was registered at www.clinicaltrials.gov as #NCT00572897.

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.

AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Circulating cardiac biomarkers and postoperative atrial fibrillation in the OPERA trial.

BACKGROUND: 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. METHODS: Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at enrollment, on the morning of cardiac surgery, at end surgery, and 2 days postsurgery in 562 patients undergoing cardiac surgery, randomized to perioperative supplementation with oral fish oil or placebo in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial (OPERA). The primary endpoint was incident POAF lasting ≥ 30 s, centrally adjudicated and confirmed electrocardiographically. RESULTS: Higher levels of NT-proBNP and hs-cTnT before surgery were associated with older age, renal or cardiac dysfunction and EuroSCORE. NT-proBNP peaked on postoperative day 2 (2172 [1238-3758] ng/L, median [Q1-Q3]), while hs-cTnT peaked at the end of surgery (373 [188-660] ng/L). Fish oil supplementation did not alter the time course of the cardiac biomarkers (P > 0.05). Concentrations of NT-proBNP or hs-cTnT, on the morning of surgery, or changes in their level between morning of surgery and postsurgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics. CONCLUSION: Among patients undergoing cardiac surgery, NT-proBNP and hs-cTnT are related to clinical and surgical characteristics, have different perioperative time courses but are not independently associated with risk of POAF.

Plasma n-3 polyunsaturated fatty acids in chronic heart failure in the GISSI-Heart Failure Trial: relation with fish intake, circulating biomarkers, and mortality.

UNLABELLED: 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.

Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis.

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ≥ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant.

Single agent bevacizumab for myelofibrosis: results of the Myeloproliferative Disorders Research Consortium Trial.

The myeloproliferative neoplasm, myelofibrosis, is a morbid and frequently fatal illness encompassing primary myelofibrosis, and end-stage essential thrombocythemia and polycythemia. Bevacizumab (15 mg/kg intravenous (i.v.) every 21 days) was tested in a phase II international trial conducted by the Myeloproliferative Disorders Research Consortium. Thirteen patients were enrolled in the first stage of this 2-stage trial. Among the 11 patients who received therapy, only 3 received more than 4 cycles of therapy; none of the patients achieved an objective response. Furthermore, significant toxicity, not directly related to the vascular or gastrointestinal events typically associated with the anti-VEGF monoclonal antibody preparation in other disease states, was observed. Lack of objective responses coupled with toxicity led to the decision to terminate the study early. If future studies incorporate bevacizumab in combination therapy for myelofibrosis, more modest doses should be considered. (clinicaltrials.gov Identifier 00667277).

Nutrient reference values for bioactives: new approaches needed? A conference report.

Nutrients can be classified as either "essential" or "non-essential," the latter are also termed bioactive substances. Whereas the absence of essential nutrients from the diet results in overt deficiency often times with moderate to severe physiological decrements, the absence of bioactive substances from the diet results in suboptimal health. Nutrient reference values are set by Codex Alimentarius and regulatory bodies in many countries, mostly for essential nutrients with recommended daily intakes. The IOM in the United States has defined a set of four DRIs that, when data are appropriate, include an EAR, a RDA that is derived from the EAR, an AI for nutrients without appropriate data to identify an EAR, and an UL. From the RDA, the United States derives a labeling value called the DV, which applies to older children and most adults. In Codex, the equivalents of the DVs are the NRVs to be used in calculating percentage values on food labels. Nothing in the IOM documents specifies that labeling values can be set only for what have been defined to date as essential nutrients. Indeed, the US Food and Drug Administration sets a labeling value for dietary fiber based on the IOM AI for this ingredient. This conference explores the definitions, concepts, and data on two of the best examples of bioactive substances that, perhaps, should have NRVs: lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids.

Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial.

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 Post-operative 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.

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

BACKGROUND: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. FINDINGS: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. INTERPRETATION: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. FUNDING: None.

The ω-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial--rationale and design.

Postoperative atrial fibrillation/flutter (PoAF) commonly complicates cardiac surgery, occurring in 25% to 60% of patients. Postoperative atrial fibrillation/flutter is associated with significant morbidity, higher long-term mortality, and increased health care costs. Novel preventive therapies are clearly needed. In experiments and short-term trials, seafood-derived long-chain ω-3 polyunsaturated fatty acids (PUFAs) influence several risk factors that might reduce risk of PoAF. A few small and generally underpowered trials have evaluated effects of ω-3-PUFAs supplementation on PoAF with mixed results. The OPERA trial is an appropriately powered, investigator-initiated, randomized, double-blind, placebo-controlled, multinational trial to determine whether perioperative oral ω-3-PUFAs reduces occurrence of PoAF in patients undergoing cardiac surgery. Additional aims include evaluation of resource use, biologic pathways and mechanisms, postoperative cognitive decline, and safety. Broad inclusion criteria encompass a "real-world" population of outpatients and inpatients scheduled for cardiac surgery. Treatment comprises a total preoperative loading dose of 8 to 10 g of ω-3-PUFAs or placebo divided over 2 to 5 days, followed by 2 g/d until hospital discharge or postoperative day 10, whichever comes first. Based on anticipated 30% event rate in controls, total enrollment of 1,516 patients (758 per treatment arm) will provide 90% power to detect 25% reduction in PoAF. The OPERA trial will provide invaluable evidence to inform biologic pathways; proof of concept that ω-3-PUFAs influence cardiac arrhythmias; and potential regulatory standards and clinical use of this simple, inexpensive, and low-risk intervention to prevent PoAF.