Alice M. Mascette

Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

BACKGROUND Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.The National Heart, Lung, and Blood Institute convened an expert panel April 28-29, 2008 to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiologic and clinical literature about AF, and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: 1) Enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; 2) Improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; 3) Improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural and electrical remodeling markers; 4) Develop additional animal models reflective of the pathophysiology of human AF; 5) Conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and 6) Conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Sudden Cardiac Death Prediction and Prevention Report From a National Heart, Lung, and Blood Institute and Heart Rhythm Society Workshop

Despite the significant decline in coronary artery disease (CAD) mortality in the second half of the 20th century,1 sudden cardiac death (SCD) continues to claim 250 000 to 300 000 US lives annually.2 In North America and Europe the annual incidence of SCD ranges between 50 to 100 per 100 000 in the general population.3,–,6 Because of the absence of emergency medical response systems in most world regions, worldwide estimates are currently not available.7 However, even in the presence of advanced first responder systems for resuscitation of out-of-hospital cardiac arrest, the overall survival rate in a recent North American analysis was 4.6%.8 SCD can manifest as ventricular tachycardia (VT), ventricular fibrillation (VF), pulseless electric activity (PEA), or asystole. In a significant proportion of patients, SCD can present without warning or a recognized triggering mechanism. The mean age of those affected is in the mid 60s, and at least 40% of patients will suffer SCD before the age of 65.4 Consequently, enhancement of methodologies for prediction and prevention of SCD acquires a unique and critical importance for management of this significant public health issue. Prediction and prevention of SCD is an area of active investigation, but considerable challenges persist that limit the efficacy and cost-effectiveness of available methodologies.7,9,10 It was recognized early on that optimization of SCD risk stratification will require integration of multi-disciplinary efforts at the bench and bedside, with studies in the general population.11,–,13 This integration has yet to be effectively accomplished. There is also increasing awareness that more investigation needs to be directed toward identification of early predictors of SCD.14 Significant advancements have occurred for risk prediction in the inherited channelopathies15,–,17 and …

Randomized Trial of Percutaneous Coronary Intervention for Subacute Infarct-Related Coronary Artery Occlusion to Achieve Long-Term Patency and Improve Ventricular Function. The Total Occlusion Study of Canada (TOSCA)-2 Trial

Background— In the present study, we sought to determine whether opening a persistently occluded infarct-related artery (IRA) by percutaneous coronary intervention (PCI) in patients beyond the acute phase of myocardial infarction (MI) improves patency and indices of left ventricular (LV) size and function. Methods and Results— Between May 2000 and July 2005, 381 patients with an occluded native IRA 3 to 28 days after MI (median 10 days) were randomized to PCI with stenting (PCI) or optimal medical therapy alone. Repeat coronary and LV angiography was performed 1 year after randomization (n=332, 87%). Coprimary end points were IRA patency and change in LV ejection fraction. Secondary end points included change in LV end-systolic and end-diastolic volume indices and wall motion. PCI was successful in 92%. At 1 year, 83% of PCI versus 25% of medical therapy–only patients had a patent IRA (P<0.001). LV ejection fraction increased significantly (P<0.001) in both groups, with no between-group difference: PCI 4.2±8.9 (n=150) versus medical therapy 3.5±8.2 (n=136; P=0.47). Median change (interquartile range) in LV end-systolic volume index was −0.5 (−9.3 to 5.0) versus 1.0 (−5.7 to 7.3) mL/m2 (P=0.10), whereas median change (interquartile range) in LV end-diastolic volume index was 3.2 (−8.2 to 13.3) versus 5.3 (−4.6 to 23.2) mL/m2 (P=0.07) in the PCI (n=86) and medical therapy–only (n=76) groups, respectively. Conclusions— PCI with stenting of a persistently occluded IRA in the subacute phase after MI effectively maintains long-term patency but has no effect on LV ejection fraction. On the basis of these findings and the lack of clinical benefit in the main Occluded Artery Trial, routine PCI is not recommended for stable patients with a persistently occluded IRA after MI.

Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis

BACKGROUND Pain management in patients with osteoarthritis or rheumatoid arthritis often requires long-term use of nonsteroidal antiinflammatory drugs (NSAIDs). However, the relative cardiovascular safety of these therapies remains uncertain. METHODS The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial will evaluate the cardiovascular safety of celecoxib, ibuprofen, and naproxen. Approximately 20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for, or with, established cardiovascular disease will be randomized in this double-blind, triple dummy, multinational, multicenter study. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial will continue until 762 primary events occur with at least 18 months follow-up. Noninferiority of any of the regimens will require a 97.5% upper CI of the hazard ratio (HR) < or =1.33 and point estimate < or =1.12 for both intent-to-treat (ITT) and modified ITT populations. CONCLUSION PRECISION, the first study of patients with high cardiovascular risk chronically treated with a cyclooxygenase-2 selective inhibitor or nonselective NSAID, will define the relative cardiovascular safety profile of celecoxib, ibuprofen, and naproxen and provide data to help guide NSAID use for pain management for this population.

Publication of trials funded by the National Heart, Lung, and Blood Institute.

BACKGROUND Rapid publication of clinical trials is essential in order for the findings to yield maximal benefits for public health and scientific progress. Factors affecting the speed of publication of the main results of government-funded trials have not been well characterized. METHODS We analyzed 244 extramural randomized clinical trials of cardiovascular interventions that were supported by the National Heart, Lung, and Blood Institute (NHLBI). We selected trials for which data collection had been completed between January 1, 2000, and December 31, 2011. Our primary outcome measure was the time between completion of the trial and publication of the main results in a peer-reviewed journal. RESULTS As of March 31, 2012, the main results of 156 trials (64%) had been published (Kaplan-Meier median time to publication, 25 months, with 57% published within 30 months). Trials that focused on clinical events were published more rapidly than those that focused on surrogate measures (median, 9 months vs. 31 months; P<0.001). The only independent predictors of more rapid publication were a focus on clinical events rather than surrogate end points (adjusted publication rate ratio, 2.11; 95% confidence interval, 1.26 to 3.53; P=0.004) and higher costs of conducting the trial, up to a threshold of approximately

Recommendations of the National Heart, Lung, and Blood Institute Working Group on Future Direction in Cardiac Surgery

5 million (P<0.001). The 37 trials that focused on clinical events and cost at least

Prevention of Atrial Fibrillation

5 million accounted for 67% of the funds spent on clinical trials but received 82% of the citations. After adjustment of the analysis for a focus on clinical events and for cost, trial results that were classified as positive were published more quickly than those classified as negative. CONCLUSIONS Results of less than two thirds of NHLBI-funded randomized clinical trials of cardiovascular interventions were published within 30 months after completion of the trial. Trials that focused on clinical events were published more quickly than those that focused on surrogate end points. (Funded by the National Heart, Lung, and Blood Institute.).

Summary of NIH Medical-Surgical Emergency Research Roundtable Held on April 30 to May 1, 2009

New surgical procedures, imaging modalities, and medical devices have improved therapy for many patients and made treatment possible for others who have had few options in the past. In February 2004, the National Heart, Lung, and Blood Institutes (NHLBI) Advisory Council proposed that the institute evaluate the status and future directions in cardiac surgery. In response to this recommendation, the NHLBI convened a working group of cardiac surgeons on May 7 and 8, 2004, to assess the state of cardiac surgery research, identify critical gaps in current knowledge, determine areas of opportunity, and obtain specific recommendations for future research activities. The working group discussed surgical revascularization, novel surgical approaches, valvular research directions, biotechnology and cell-based therapy, heart failure, imaging modalities, and barriers to clinical research and presents its recommendations here.

Biomarker-guided therapies in heart failure: a forum for unified strategies.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.The National Heart, Lung, and Blood Institute convened an expert panel April 28-29, 2008 to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiologic and clinical literature about AF, and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: 1) Enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; 2) Improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; 3) Improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural and electrical remodeling markers; 4) Develop additional animal models reflective of the pathophysiology of human AF; 5) Conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and 6) Conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.