Sudden cardiac death in patients with ischemic heart failure undergoing coronary artery bypass grafting results from the STICH randomized clinical trial (Surgical Treatment for Ischemic Heart Failure)

Background—The risk of sudden cardiac death (SCD) in patients with heart failure following CABG has not been examined in a contemporary clinical trial of surgical revascularization. This analysis describes the incidence, timing and clinical predictors of SCD after CABG. Methods—Patients enrolled in the Surgical Treatment of Ischemic Heart Failure (STICH) trial who underwent CABG with or without surgical ventricular reconstruction (SVR) were included. We excluded patients with prior ICD and those randomized only to medical therapy. The primary outcome was SCD as adjudicated by a blinded committee. A Cox model was used to examine and identify predictors of SCD. The Fine and Gray method was used to estimate the incidence of SCD accounting for the competing risk of other deaths. Results—Over a median follow-up of 46 months, 113 patients of 1411 patients who received CABG without (n = 934) or with SVR (n = 477) had SCD; 311 died of other causes. The mean LVEF at enrollment was 28±9%. The 5-year cumulative incidence of SCD was 8.5%. Patients who had SCD and those who did not die were younger and had fewer comorbid conditions than those who died for reasons other than SCD. In the first 30 days after CABG, SCD (n=5) accounted for 7% of all deaths. The numerically greatest monthly rate of SCD was in the 31-90 day time period. In a multivariable analysis including baseline demographics, risk factors, coronary anatomy and LV function, ESVI and BNP were most strongly associated with SCD. Conclusions—The monthly risk of SCD shortly after CABG among patients with a low LVEF is highest between the first and third month, suggesting that risk stratification for SCD should occur early in the postoperative period, particularly in patients with increased preoperative ESVI and/or BNP

Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial.

Importance: Iron deficiency is present in approximately 50% of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) and is an independent predictor of reduced functional capacity and mortality. However, the efficacy of inexpensive readily available oral iron supplementation in heart failure is unknown. Objective: To test whether therapy with oral iron improves peak exercise capacity in patients with HFrEF and iron deficiency. Design, Setting, and Participants: Phase 2, double-blind, placebo-controlled randomized clinical trial of patients with HFrEF ( Interventions: Oral iron polysaccharide (n = 111) or placebo (n = 114), 150 mg twice daily for 16 weeks. Main Outcomes and Measures: The primary end point was a change in peak oxygen uptake (V̇o2) from baseline to 16 weeks. Secondary end points were change in 6-minute walk distance, plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and health status as assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ, range 0-100, higher scores reflect better quality of life). Results: Among 225 randomized participants (median age, 63 years; 36% women) 203 completed the study. The median baseline peak V̇o2 was 1196 mL/min (interquartile range [IQR], 887-1448 mL/min) in the oral iron group and 1167 mL/min (IQR, 887-1449 mL/min) in the placebo group. The primary end point, change in peak V̇o2 at 16 weeks, did not significantly differ between the oral iron and placebo groups (+23 mL/min vs -2 mL/min; difference, 21 mL/min [95% CI, -34 to +76 mL/min]; P = .46). Similarly, at 16 weeks, there were no significant differences between treatment groups in changes in 6-minute walk distance (-13 m; 95% CI, -32 to 6 m), NT-proBNP levels (159; 95% CI, -280 to 599 pg/mL), or KCCQ score (1; 95% CI, -2.4 to 4.4), all P \u3e .05. Conclusions and Relevance: Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks. These results do not support use of oral iron supplementation in patients with HFrEF. Trial Registration: clinicaltrials.gov Identifier: NCT02188784

Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01685840

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Coronary bypass surgery with or without surgical ventricular reconstruction

Coronary bypass surgery with or without surgical ventricular reconstruction. Jones RH, Velazquez EJ, Michler RE, Sopko G, Oh JK, O'Connor CM, Hill JA, Menicanti L, Sadowski Z, Desvigne-Nickens P, Rouleau JL, Lee KL; STICH Hypothesis 2 Investigators. Collaborators (379)Bochenek A, Krejca M, Trusz-Gluza M, Wita K, Zembala M, Przybylski R, Kukulski T, Cherniavsky A, Marchenko A, Romanov A, Wos S, Deja M, Golba K, Kot J, Rao V, Iwanochko M, Renton J, Hemeon S, Rogowski J, Rynkiewicz A, Betlejewski P, Sun B, Crestanello J, Binkley P, Chang J, Ferrazzi P, Gavazzi A, Senni M, Sadowski J, Kapelak B, Sobczyk D, Wrobel K, Pirk J, Jandova R, Velazquez E, Smith P, Milano C, Adams P, Menicanti L, Di Donato M, Castelvecchio S, Dagenais F, Dussault G, Dupree C, Sheridan B, Schuler C, Yii M, Prior D, Mack J, Racine N, Bouchard D, Ducharme A, Lavoignat J, Maurer G, Grimm M, Lang I, Adlbrecht C, Religa Z, Biederman A, Szwed H, Sadowski Z, Rajda M, Ali I, Howlett J, MacFarlane M, Siepe M, Beyersdorf F, Cuerten C, Wiechowski S, Mokrzycki K, Hill J, Beaver T, Olitsky D, Bernstein V, Janusz M, O'Neill V, Grayburn P, Hebeler R, Hamman B, Aston S, Gradinac S, Vukovic M, Djokovic L, Benetis R, Jankauskiene L, Friedrich I, Buerke M, Paraforos A, Quaini E, Cirillo M, Chua L, Lim C, Kwok B, Kong S, Stefanelli G, Labia C, Bergh C, Gustafsson C, Daly R, Rodeheffer R, Nelson S, Maitland A, Isaac D, Holland M, Di Benedetto G, Attisano T, Sievers H, Schunkert H, Stierle U, Haddad H, Hendry P, Donaldson J, Birjiniuk V, Harrington M, Nawarawong W, Woragidpunpol S, Kuanprasert S, Mekara W, Konda S, Neva C, Hathaway W, Groh M, Blakely J, Lamy A, Demers C, Rizzo T, Drazner M, DiMaio J, Joy J, Benedik J, Marketa K, Beghi C, De Blasi M, Helou J, Dallaire S, Kron I, Kern J, Bergin J, Phillips J, Aldea G, Verrier E, Harrison L, Piegas L, Paulista P, Farsky P, Veiga-Kantorowitz C, Philippides G, Shemin R, Thompson J, White H, Alison P, Stewart R, Clapham T, Rich J, Herre J, Pine L, Kalil R, Nesralla I, Santos M, Pereira de Moraes M, Michler R, Swayze R, Arnold M, McKenzie N, Smith J, Nicolau J, Oliveira S, Stolf N, Ferraz M, Filgueira J, Batlle C, Rocha A, Gurgel Camara A, Huynh T, Cecere R, Finkenbine S, St-Jacques B, Ilton M, Wittstein I, Conte J, Breton E, Panza J, Boyce S, McNulty M, Starnes V, Lopez B, Biederman R, Magovern J, Dean D, Grant S, Hammon J, Wells G, De Pasquale C, Knight J, Healy H, Maia L, Souza A, McRae R, Pierson M, Gullestad L, Sorensen G, Murphy E, Ravichandran P, Avalos K, Horowitz J, Owen E, Ascheim D, Naka Y, Yushak M, Gerometta P, Arena V, Borghini E, Johnsson P, Ekmehag B, Engels K, Rosenblum W, Swayze R, Amanullah A, Krzeminska-Pakula M, Drozdz J, Larbalestier R, Wang X, Busmann C, Horkay F, Szekely L, Keltai M, Hetzer R, Knosalla C, Nienkarken T, Chiariello L, Nardi P, Arom K, Ruengsakulrach P, Hayward C, Jansz P, Stuart S, Oto O, Sariomanoglu O, Dignan R, French J, Gonzalez M, Edes I, Szathmarine V, Yakub M, Sarip S, Alotti N, Lupkovics G, Smedira N, Pryce J, Cokkinos D, Palatianos G, Kremastinos D, Stewart R, Rinkes L, Esrig B, Baptiste M, Booth D, Ramaiah C, Ferraris V, Menon S, Martin L, Couper G, Rosborough D, Vanhaecke J, Strijckmans A, Carson P, Dupree C, Miller A, Pina I, Selzman C, Wertheimer J, Goldstein S, Cohn F, Hlatky M, Kennedy K, Rankin S, Robbins R, Zaret B, Rouleau J, Desvigne-Nickens P, Jones R, Lee K, Michler R, O'Connor C, Oh J, Rankin G, Velazquez E, Hill J, Beyersdorf F, Bonow R, Desvigne-Nickens P, Jones R, Lee K, Oh J, Panza J, Rouleau J, Sadowski Z, Velazquez E, White H, Jones R, Velazquez E, O'Connor C, Rankin G, Sellers M, Sparrow-Parker B, McCormick A, Albright J, Dandridge R, Rittenhouse L, Wagstaff D, Wakeley N, Burns S, Williams M, Bailey D, Parrish L, Daniels H, Grissom G, Medlin K, Lee K, She L, McDaniel A, Lokhnygina Y, Greene D, Moore V, Pohost G, Agarwal S, Apte P, Bahukha P, Chow M, Chu X, Doyle M, Forder J, Ocon M, Reddy V, Santos N, Tripathi R, Varadarajan P, Oh J, Blahnik F, Bruce C, Lin G, Manahan B, Miller D, Miller F, Pellikka P, Springer R, Welper J, Wiste H, Mark D, Anstrom K, Baloch K, Burnette A, Clapp-Channing N, Cowper P, Davidson-Ray N, Drew L, Harding T, Hunt V, Knight D, Patterson A, Redick T, Sanderford B, Feldman A, Bristow M, Chan T, Diamond M, Maisel A, Mann D, McNamara D, Bonow R, Berman D, Helmer D, Holly T, Leonard S, Woods M, Panza J, McNulty M, Grayburn P, Aston S. SourceDuke Clinical Research Institute, Duke University Medical Center, Durham, NC 27710, USA. [email protected] Abstract BACKGROUND: Surgical ventricular reconstruction is a specific procedure designed to reduce left ventricular volume in patients with heart failure caused by coronary artery disease. We conducted a trial to address the question of whether surgical ventricular reconstruction added to coronary-artery bypass grafting (CABG) would decrease the rate of death or hospitalization for cardiac causes, as compared with CABG alone. METHODS: Between September 2002 and January 2006, a total of 1000 patients with an ejection fraction of 35% or less, coronary artery disease that was amenable to CABG, and dominant anterior left ventricular dysfunction that was amenable to surgical ventricular reconstruction were randomly assigned to undergo either CABG alone (499 patients) or CABG with surgical ventricular reconstruction (501 patients). The primary outcome was a composite of death from any cause and hospitalization for cardiac causes. The median follow-up was 48 months. RESULTS: Surgical ventricular reconstruction reduced the end-systolic volume index by 19%, as compared with a reduction of 6% with CABG alone. Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in the two study groups. However, no significant difference was observed in the primary outcome, which occurred in 292 patients (59%) who were assigned to undergo CABG alone and in 289 patients (58%) who were assigned to undergo CABG with surgical ventricular reconstruction (hazard ratio for the combined approach, 0.99; 95% confidence interval, 0.84 to 1.17; P=0.90). CONCLUSIONS: Adding surgical ventricular reconstruction to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance or with a reduction in the rate of death or hospitalization for cardiac causes. (ClinicalTrials.gov number, NCT00023595.

Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF

Machine learning evaluation of LV outflow obstruction in hypertrophic cardiomyopathy using three-chamber cardiovascular magnetic resonance

Left ventricular outflow tract obstruction (LVOTO) is common in hypertrophic cardiomyopathy (HCM), but relationships between anatomical metrics and obstruction are poorly understood. We aimed to develop machine learning methods to evaluate LVOTO in HCM patients and quantify relationships between anatomical metrics and obstruction. This retrospective analysis of 1905 participants of the HCM Registry quantified 11 anatomical metrics derived from 14 landmarks automatically detected on the three-chamber long axis cine CMR images. Linear and logistic regression was used to quantify strengths of relationships with the presence of LVOTO (defined by resting Doppler pressure drop of > 30 mmHg), using the area under the receiver operating characteristic (AUC). Intraclass correlation coefficients between the network predictions and three independent observers showed similar agreement to that between observers. The distance from anterior mitral valve leaflet tip to basal septum (AML-BS) was most highly correlated with Doppler pressure drop (R(2) = 0.19, p < 10(-5)). Multivariate stepwise regression found the best predictive model included AML-BS, AML length to aortic valve diameter ratio, AML length to LV width ratio, and midventricular septal thickness metrics (AUC 0.84). Excluding AML-BS, metrics grouped according to septal hypertrophy, LV geometry, and AML anatomy each had similar associations with LVOTO (AUC 0.71, 0.71, 0.68 respectively, p = ns), significantly less than their combination (AUC 0.77, p < 0.05 for each). Anatomical metrics derived from a standard three-chamber CMR cine acquisition can be used to highlight risk of LVOTO, and suggest further investigation if necessary. A combination of geometric factors is required to provide the best risk prediction

Research Priorities in Atrial Fibrillation Screening A Report From a National Heart, Lung, and Blood Institute Virtual Workshop

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF

Differences in NT-proBNP Response and Prognosis in Men and Women With Heart Failure With Reduced Ejection Fraction.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840

Research priorities in the secondary prevention of atrial fibrillation: a National Heart, Lung, and Blood Institute virtual workshop report

There has been sustained focus on the secondary prevention of coronary heart disease and heart failure; yet, apart from stroke prevention, the evidence base for the secondary prevention of atrial fibrillation (AF) recurrence, AF progression, and AF-related complications is modest. Although there are multiple observational studies, there are few large, robust, randomized trials providing definitive effective approaches for the secondary prevention of AF. Given the increasing incidence and prevalence of AF nationally and internationally, the AF field needs transformative research and a commitment to evidenced-based secondary prevention strategies. We report on a National Heart, Lung, and Blood Institute virtual workshop directed at identifying knowledge gaps and research opportunities in the secondary prevention of AF. Once AF has been detected, lifestyle changes and novel models of care delivery may contribute to the prevention of AF recurrence, AF progression, and AF-related complications. Although benefits seen in small subgroups, cohort studies, and selected randomized trials are impressive, the widespread effectiveness of AF secondary prevention strategies remains unknown, calling for development of scalable interventions suitable for diverse populations and for identification of subpopulations who may particularly benefit from intensive management. We identified critical research questions for 6 topics relevant to the secondary prevention of AF: (1) weight loss; (2) alcohol intake, smoking cessation, and diet; (3) cardiac rehabilitation; (4) approaches to sleep disorders; (5) integrated, team-based care; and (6) nonanticoagulant pharmacotherapy. Our goal is to stimulate innovative research that will accelerate the generation of the evidence to effectively pursue the secondary prevention of AF.Emelia J. Benjamin, Sana M. Al-Khatib, Patrice Desvigne-Nickens, Alvaro Alonso, Luc Djoussé, Daniel E. Forman, Anne M. Gillis, Jeroen M.L. Hendriks, Mellanie True Hills, Paulus Kirchhof, Mark S. Link, Gregory M. Marcus, Reena Mehra, Katherine T. Murray, Ratika Parkash, Ileana L. Piña, Susan Redline, Michiel Rienstra, Prashanthan Sanders, Virend K. Somers, David R. Van Wagoner, Paul J. Wang, Lawton S. Cooper, Alan S. G