Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

AIMS: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. METHODS AND RESULTS: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years). CONCLUSIONS: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.

The Need for Fiber Addition in Symptomatic Heart Failure (FEAST-HF): A Randomized Controlled Pilot Trial.

Background: Preclinical and observational studies suggest that the gut microbiome plays a role in the pathogenesis of heart failure (HF); the gut microbiome may be modified by fermentable dietary fibre (FDF). The Need for Fiber Addition in Symptomatic Heart Failure (FEAST-HF) trial evaluated feasibility of recruitment and supplementation with FDF in HF and whether FDF (acacia), compared to control, reduced the level of N-terminal pro-b-type natriuretic peptide (NT-proBNP) and growth stimulation expressed gene 2 (ST2), and produced changes in the gut microbiome. Methods: Participants were randomly allocated 1:1:1 to either of the intervention arms (5 g/d or 10 g/d acacia) or to the control arm (10 g/d microcrystalline cellulose (MCC; nonfermentable active control). Adherence and tolerance were assessed, and clinical events were monitored for safety. All outcomes (NT-proBNP, ST2, New York Heart Association class, Kansas City Cardiomyopathy Questionnaire scores, 6-minute walk test score, gut microbiome) were measured at baseline, and at 6 and 12 weeks. Results: Between September 13, 2018 and December 16, 2021, 51 patients were randomly allocated to either MCC (n = 18), acacia 5 g daily (n = 13), or acacia 10 g daily (n = 18). No differences occurred between either dose of acacia and MCC in NT-proBNP level, ST2, New York Heart Association class, or questionnaire scores over 12 weeks. Dietary treatment arms had a negligible impact on microbial communities. No safety, tolerability, or adherence issues were observed. Conclusions: Dietary supplementation with acacia gum was both safe and well tolerated in ambulatory patients with HF; however, it did not change NT-proBNP level, ST2, or the composition of the gut microbiome.ClinicalTrials.gov: NCT03409926.

Contexte: Des études précliniques et observationnelles donnent à penser que le microbiome intestinal joue un rôle dans la pathogenèse de l'insuffisance cardiaque (IC). Or, ce microbiome pourrait être modifié par la consommation de fibres alimentaires fermentescibles (FAF). L'essai pilote contrôlé avec répartition aléatoire FEAST-HF (pour The Need forFiberAddition inSymptomaticHeartFailure) visait à évaluer la possibilité d'administrer un supplément de FAF (l'acacia) et à déterminer si celui-ci entraîne une réduction du taux du propeptide natriurétique de type B N-terminal (NT-proBNP) et du récepteur ST2 (growth stimulation expressed gene 2) ou une modification du microbiome intestinal comparativement au placebo. Méthodologie: Les participants ont été répartis de façon aléatoire selon un rapport 1:1:1 dans l'un des groupes d'intervention (recevant 5 g/jour ou 10 g/jour d'acacia) ou dans le groupe témoin (recevant 10 g/jour de cellulose microcristalline [CMC], une fibre de référence non fermentescible). La tolérance et l'observance du traitement ont été évaluées, et les événements cliniques ont été surveillés pour évaluer l'innocuité. Tous les indicateurs (NT-proBNP, ST2, classe d'IC selon l'échelle de la New York Heart Association, score au questionnaire de cardiomyopathie de Kansas City, score à un test de marche de 6 minutes et microbiome intestinal) ont été évalués au début de l'étude, à la semaine 6 et à la semaine 12. Résultats: Entre le 13 septembre 2018 et le 16 décembre 2021, 51 patients ont pris, après répartition aléatoire, de la CMC (n = 18), 5 g d'acacia par jour (n = 13) ou 10 g d'acacia par jour (n = 18). Aucune différence n'a été observée quant au taux de NT-proBNP ou de ST2, à la classe d'IC selon la New York Heart Association ou aux scores au questionnaire entre les groupes prenant l'une ou l'autre des doses d'acacia et le groupe prenant la CMC au cours d'une période de 12 semaines. L'effet sur la flore microbienne était négligeable dans les groupes de traitement alimentaire. Par ailleurs, aucun problème lié à l'innocuité, à la tolérabilité ou à l'observance du traitement n'a été observé. Conclusions: Les suppléments alimentaires d'acacia (gomme arabique) sont sûrs et bien tolérés; toutefois, ces suppléments n'ont pas entraîné de changement dans les taux de NT-proBNP ou de ST2, ni dans la composition du microbiome intestinal.ClinicalTrials.gov : NCT03409926.

Assessment of Biomarkers of Myocardial injury, Inflammation, and Renal Function in Heart Failure With Reduced Ejection Fraction: The VICTORIA Biomarker Substudy.

BACKGROUND: Circulating biomarkers may be useful in understanding prognosis and treatment efficacy in heart failure with reduced ejection fraction. In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat, a soluble guanylate cyclase stimulator, decreased the primary outcome of cardiovascular death or heart failure hospitalization in heart failure with reduced ejection fraction. We evaluated biomarkers of cardiac injury, inflammation, and renal function for associations with outcomes and vericiguat treatment effect. METHODS AND RESULTS: High-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and cystatin C were measured at baseline and 16 weeks. Associations of biomarkers with the primary outcome and its components were estimated. Interaction with study treatment was tested. Changes in biomarkers over time were examined by study treatment. One or more biomarkers were measured in 4652 (92%) of 5050 participants at baseline and 4063 (81%) at 16 weeks. After adjustment, higher values of hs-cTnT, growth differentiation factor-15, and interleukin-6 were associated with the primary outcome, independent of N-terminal pro-B-type natriuretic peptide. Higher hs-cTnT values were associated with a hazard ratio per log standard deviation of 1.21 (95% confidence interval 1.14-1.27). A treatment interaction with vericiguat was evident with hs-cTnT and cardiovascular death (P = .04), but not HF hospitalization (P = .38). All biomarkers except cystatin C decreased over 16 weeks and no relationship between treatment assignment and changes in biomarker levels was observed. CONCLUSIONS: hs-cTnT, growth differentiation factor-15, and interleukin-6 levels were associated with risk of the primary outcome in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction). Uniquely, lower hs-cTnT was associated with a lower rate of cardiovascular death but not HF hospitalization after treatment with vericiguat.

Efficacy and safety of vericiguat in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan: insights from the VICTORIA trial.

AIM: We assessed a subset of the 5040 patients in VICTORIA receiving sacubitril/valsartan, either at randomization (n = 731) or post-randomization drop-in use (n = 425), to evaluate the relationship between the efficacy and safety of combination therapy with vericiguat. METHODS AND RESULTS: The efficacy of vericiguat on the primary composite endpoint, heart failure (HF) hospitalization, and all-cause mortality was assessed. Safety outcomes included symptomatic hypotension, syncope, worsening renal function, and hyperkalaemia. At randomization, 731 patients received sacubitril/valsartan; they were more frequently from Western Europe or North America, had lower ejection fraction and systolic blood pressure, and more use of triple background HF therapy (65.9% vs. 58.6%), biventricular pacemakers (17.9% vs. 14.1%), or implantable cardioverter defibrillators (42.3% vs. 25.3%). For patients on versus not on sacubitril/valsartan at randomization, adjusted hazard ratios (95% confidence intervals) for vericiguat's treatment effect on the primary composite outcome, cardiovascular death, and HF hospitalization were 0.92 (0.71-1.19) versus 0.89 (0.80-0.98), 0.71 (0.45-1.12) versus 0.95 (0.82-1.11), and 0.98 (0.74-1.29) versus 0.87 (0.78-0.98), respectively. No significant interaction existed between sacubitril/valsartan and vericiguat's treatment effect (p-values for interaction: 0.81, 0.23 and 0.47, respectively). Post-randomization, more drop-in sacubitril/valsartan use occurred in those assigned to placebo (n = 238) versus vericiguat (n = 187) (p = 0.007). Symptomatic hypotension (21.0% vs. 23.1%; p = 0.41), renal dysfunction (29.9% vs. 31.9%; p = 0.50), and hyperkalaemia (10.3% vs. 7.9%; p = 0.20) in patients receiving sacubitril/valsartan (n = 992) for ≥3 months were not different by treatment arm. CONCLUSIONS: Concomitant use of sacubitril/valsartan for at least 3 months did not alter the efficacy of vericiguat and was similarly safe and tolerated in both study arms. Sacubitril/valsartan was initiated more frequently after randomization in patients assigned to placebo versus vericiguat. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02861534.

Clinical Phenotypes of Heart Failure across the spectrum of Ejection Fraction: A Cluster Analysis.

INTRODUCTION: Heart failure (HF), and especially HF with preserved ejection fraction (HFpEF), remains a challenging condition to define. The heterogenous nature of this population may be related to a variety of underlying etiologies interacting myocardial dysfunction. METHOD: Alberta HEART study was a prospective, observational cohort that enrolled participants along the spectrum of heart failure including: healthy controls, people at risk of HF, and patients with HF and preserved (HFpEF) or reduced ejection fraction (HFrEF). We aimed to explore phenotypes of patients with HF and at-risk of developing HF. Utilising 27 detailed clinical, echocardiographic and biomarker variables, latent class analysis with and without multiple imputation was undertaken to identify distinct clinical phenotypes. RESULTS: Of 621 participants, 191 (30.8%) and 169 (27.2%) were adjudicated by cardiologists to have HFpEF and HFrEF respectively. In the overall cohort, latent class analysis identified four distinct phenotypes. Phenotype A (n=152, 24.5%) was a healthy and low risk group. Phenotype B (n=129, 20.8%) demonstrated increased left ventricular mass and end-diastolic volumes, with elevated natriuretic peptides and clinical features of congestion. Phenotype C (n=128, 20.6%) was primarily characterised by obesity (80%) and normal indexed cardiac chamber sizes, low natriuretic peptide levels and minimal features of congestion.  Phenotype D (n=212, 34.1%) consisted of elderly patients with clinical features of congestions. Phenotypes B and D demonstrated the highest risk of mortality and hospitalization over a median follow-up of 3.7 years. CONCLUSION: Phenotypes with congestive features demonstrated increased risk profiles. Heart failure is a heterogenous classification which requires further work to appropriately categorise patients based on the underlying etiology or mechanism of impairment.

Reduction of dietary sodium to less than 100 mmol in heart failure (SODIUM-HF): an international, open-label, randomised, controlled trial.

BACKGROUND: Dietary restriction of sodium has been suggested to prevent fluid overload and adverse outcomes for patients with heart failure. We designed the Study of Dietary Intervention under 100 mmol in Heart Failure (SODIUM-HF) to test whether or not a reduction in dietary sodium reduces the incidence of future clinical events. METHODS: SODIUM-HF is an international, open-label, randomised, controlled trial that enrolled patients at 26 sites in six countries (Australia, Canada, Chile, Colombia, Mexico, and New Zealand). Eligible patients were aged 18 years or older, with chronic heart failure (New York Heart Association [NYHA] functional class 2-3), and receiving optimally tolerated guideline-directed medical treatment. Patients were randomly assigned (1:1), using a standard number generator and varying block sizes of two, four, or six, stratified by site, to either usual care according to local guidelines or a low sodium diet of less than 100 mmol (ie, <1500 mg/day). The primary outcome was the composite of cardiovascular-related admission to hospital, cardiovascular-related emergency department visit, or all-cause death within 12 months in the intention-to-treat (ITT) population (ie, all randomly assigned patients). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT02012179, and is closed to accrual. FINDINGS: Between March 24, 2014, and Dec 9, 2020, 806 patients were randomly assigned to a low sodium diet (n=397) or usual care (n=409). Median age was 67 years (IQR 58-74) and 268 (33%) were women and 538 (66%) were men. Between baseline and 12 months, the median sodium intake decreased from 2286 mg/day (IQR 1653-3005) to 1658 mg/day (1301-2189) in the low sodium group and from 2119 mg/day (1673-2804) to 2073 mg/day (1541-2900) in the usual care group. By 12 months, events comprising the primary outcome had occurred in 60 (15%) of 397 patients in the low sodium diet group and 70 (17%) of 409 in the usual care group (hazard ratio [HR] 0·89 [95% CI 0·63-1·26]; p=0·53). All-cause death occurred in 22 (6%) patients in the low sodium diet group and 17 (4%) in the usual care group (HR 1·38 [0·73-2·60]; p=0·32), cardiovascular-related hospitalisation occurred in 40 (10%) patients in the low sodium diet group and 51 (12%) patients in the usual care group (HR 0·82 [0·54-1·24]; p=0·36), and cardiovascular-related emergency department visits occurred in 17 (4%) patients in the low sodium diet group and 15 (4%) patients in the usual care group (HR 1·21 [0·60-2·41]; p=0·60). No safety events related to the study treatment were reported in either group. INTERPRETATION: In ambulatory patients with heart failure, a dietary intervention to reduce sodium intake did not reduce clinical events. FUNDING: Canadian Institutes of Health Research and the University Hospital Foundation, Edmonton, Alberta, Canada, and Health Research Council of New Zealand.

Novel multi-marker proteomics in phenotypically matched patients with ST-segment myocardial infarction: association with clinical outcomes.

Early prediction of significant morbidity or mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) represents an unmet clinical need. In phenotypically matched population of 139 STEMI patients (72 cases, 67 controls) treated with primary percutaneous coronary intervention, we explored associations between a 24-h relative change from baseline in the concentration of 91 novel biomarkers and the composite outcome of death, heart failure, or shock within 90 days. Additionally, we used random forest models to predict the 90-day outcomes. After adjustment for false discovery rate, the 90-day composite was significantly associated with concentration changes in 14 biomarkers involved in various pathophysiologic processes including: myocardial fibrosis/remodeling (collagen alpha-1, cathepsin Z, metalloproteinase inhibitor 4, protein tyrosine phosphatase subunits), inflammation, angiogenesis and signaling (interleukin 1 and 2 subunits, growth differentiation factor 15, galectin 4, trefoil factor 3), bone/mineral metabolism (osteoprotegerin, matrix extracellular phosphoglycoprotein and tartrate-resistant acid phosphatase), thrombosis (tissue factor pathway inhibitor) and cholesterol metabolism (LDL-receptor). Random forest models suggested an independent association when inflammatory markers are included in models predicting the outcomes within 90 days. Substantial heterogeneity is apparent in the early proteomic responses among patients with acutely reperfused STEMI patients who develop death, heart failure or shock within 90 days. These findings suggest the need to consider synergistic multi-biomarker strategies for risk stratification and to inform future development of novel post-myocardial infarction therapies.

The influence of comorbidities on achieving an N-terminal pro-b-type natriuretic peptide target: a secondary analysis of the GUIDE-IT trial.

AIMS: N-terminal pro-b-type natriuretic peptide (NT-proBNP) values may be influenced by patient factors beyond the severity of illness, including atrial fibrillation (AF), renal dysfunction, or increased body mass index (BMI). We hypothesized that these factors may influence the achievement of NT-proBNP targets and clinical outcomes. METHODS: A total of 894 patients with heart failure with reduced ejection fraction were enrolled in The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment trial. NT-proBNP was analysed every 3 months. RESULTS: Forty per cent of patients had AF, the median estimated glomerular filtration rate (eGFR) was 59 mL/min/1.73 m2 [interquartile range (IQR) 43-76], and median BMI was 29 kg/m2 (IQR 25-34). Patients with AF, eGFR < 60 mL/min/1.73 m2 , or a BMI < 29 kg/m2 had a higher level of NT-proBNP at randomization and over all study visits (all P values < 0.001). Over 18 months, the rate of change of NT-proBNP was less for patients with AF (compared with those without AF, P = 0.037) and patients with an eGFR < 60 mL/min/1.73 m2 (compared with eGFR > 60 mL/min/1.73 m2 , P < 0.001). The rate of change of NT-proBNP was similar for patients with a BMI above or below the median value. Using the 90 day NT-proBNP, patients with AF, lower eGFR, or lower BMI were less likely to achieve the target NT-proBNP < 1000 pg/mL than patients without AF, higher eGFR, or higher BMI, respectively. None of these differed between the Usual Care or Guided Care arm for AF, eGFR, or BMI (Pinteractions all NS). CONCLUSIONS: Patients with AF, a lower BMI, or worse renal function are less likely to achieve a lower or target NT-proBNP. Clinicians should be aware of these factors both when interpreting NT-proBNP levels and making therapeutic decisions about heart failure therapies.

Vericiguat in patients with atrial fibrillation and heart failure with reduced ejection fraction: insights from the VICTORIA trial.

AIMS: We evaluated the relation between baseline and new-onset atrial fibrillation (AF) and outcomes, and assessed whether vericiguat modified the likelihood of new-onset AF in patients with worsening heart failure (HF) with reduced ejection fraction in VICTORIA. METHODS AND RESULTS: Of 5050 patients randomized, 5010 with recorded AF status at baseline were analysed. Patients were classified into three groups: no known AF (n = 2661, 53%), history of AF alone (n = 992, 20%), and AF on randomization electrocardiogram (n = 1357, 27%). Compared with those with no AF, those with history of AF alone had a higher risk of cardiovascular death [adjusted hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.01-1.47] without excess myocardial infarction or stroke; neither type of AF was associated with a higher risk of the primary composite outcome (time to cardiovascular death or first HF hospitalization), HF hospitalizations, or all cause-death. The beneficial effect of vericiguat on the primary composite outcome and its components was evident irrespective of AF status at baseline. Over a median follow-up of 10.8 months, new-onset AF occurred in 6.1% of those with no AF and 18.3% with history of AF alone (P < 0.0001). These events were not influenced by vericiguat treatment (adjusted HR 0.93, 95% CI 0.75-1.16; P = 0.51), but were associated with an increase in the hazard of both primary and secondary outcomes. CONCLUSIONS: Atrial fibrillation was present in nearly half of this high-risk population with worsening HF. A history of AF alone at baseline portends an increased risk of cardiovascular death. Neither type of AF affected the beneficial effect of vericiguat. Development of AF post-randomization was associated with an increase in both cardiovascular death and HF hospitalization which was not influenced by vericiguat.

Long-Term Clinical Outcomes Following Revascularization in High-Risk Coronary Anatomy Patients With Stable Ischemic Heart Disease.

Background The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial failed to show a reduction in hard clinical end points with an early invasive strategy in stable ischemic heart disease (SIHD). However, the influence of left main disease and high-risk coronary anatomy was left unaddressed. In a large angiographic disease-based registry, we examined the modulating effect of revascularization on long-term outcomes in anatomically high-risk SIHD. Methods and Results 9016 patients with SIHD with high-risk coronary anatomy (3 vessel disease with ≥70% stenosis in all 3 epicardial vessels or left main disease ≥50% stenosis [isolated or in combination with other disease]) were selected for study from April 1, 2002 to March 31, 2016. The primary composite of all-cause death or myocardial infarction (MI) was compared between revascularization versus conservative management. A total of 5487 (61.0%) patients received revascularization with either coronary artery bypass graft surgery (n=3312) or percutaneous coronary intervention (n=2175), while 3529 (39.0%) patients were managed conservatively. Selection for coronary revascularization was associated with improved all-cause death/MI as well as longer survival compared with selection for conservative management (Inverse Probability Weighted hazard ratio [IPW-HR] 0.62; 95% CI 0.58 to 0.66; P<0.001; IPW-HR 0.57; 95% CI 0.53-0.61; P<0.001, respectively). Similar risk reduction was noted with percutaneous coronary intervention (IPW-HR 0.64, 95% CI 0.59-0.70, P<0.001) and coronary artery bypass graft surgery (IPW-HR 0.61; 95% CI 0.57-0.66; P<0.001). Conclusions Revascularization in patients with SIHD with high-risk coronary anatomy was associated with improved long-term outcome compared with conservative therapy. As such, coronary anatomical profile should be considered when contemplating treatment for SIHD.

N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction Study.

OBJECTIVES: The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization. BACKGROUND: Vericiguat compared with placebo reduced the primary outcome of cardiovascular death (CVD) or heart failure hospitalization (HFH) in patients with HF with reduced ejection fraction (HFrEF) in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. Because an interaction existed between treatment and the primary outcome according to pre-specified quartiles of NT-proBNP at randomization, we examined this further. METHODS: This study evaluated the NT-proBNP relationship with the primary outcome in 4,805 of 5,050 patients as a risk-adjusted, log-transformed continuous variable. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: Median NT-proBNP was 2,816 pg/ml (25th to 75th percentile: 1,556 to 5,314 pg/ml). The study treatment effect varied across the spectrum of NT-proBNP at randomization (with log2 transformation, p for interaction = 0.002). A significant association between treatment effects existed in patients with levels <4,000 pg/ml and remained evident up to 8,000 pg/ml. A 23% relative risk reduction occurred in the primary endpoint with NT-proBNP ≤4,000 pg/ml (HR: 0.77; 95% CI: 0.68 to 0.88). For NT-proBNP values ≤4,000 pg/ml (n = 3,100), the HR was 0.78 (95% CI: 0.67 to 0.90) for HFH and 0.75 (95% CI: 0.60 to 0.94) for CVD. For NT-proBNP ≤8,000 pg/ml (n = 4,133), the HR was 0.85 (95% CI: 0.76 to 0.95) for the primary outcome, 0.84 (95% CI: 0.75 to 0.95) for HFH, and 0.84 (95% CI: 0.71 to 0.99) for CVD. For NT-proBNP >8,000 pg/ml (n = 672), the HR was 1.16 (95% CI: 0.94 to 1.41) for the primary outcome. CONCLUSIONS: A reduction in the primary composite endpoint and its CVD and HFH components was observed in patients on vericiguat compared with subjects on placebo with NT-proBNP levels up to 8,000 pg/ml. This provided new insight into the benefit observed in high-risk patients with worsening HFrEF. (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Long-Term Outcomes of Complete Revascularization With Percutaneous Coronary Intervention in Acute Coronary Syndromes.

OBJECTIVES: The aim of this study was to evaluate the long-term outcomes of patients with acute coronary syndromes (ACS) with multivessel disease undergoing percutaneous coronary intervention (PCI). BACKGROUND: Controversy exists regarding the benefit of multivessel PCI across the spectrum of ACS. METHODS: A total of 9,094 patients with ACS and multivessel disease (≥70% stenosis in 2 or more major epicardial vessels) undergoing PCI from the Alberta COAPT (Contemporary Acute Coronary Syndrome Patients Invasive Treatment Strategies) registry (April 1, 2007, to March 31, 2013) were reviewed. Comparisons were made between patients who underwent complete revascularization and those with incomplete revascularization. Complete revascularization was defined as multivessel PCI with a residual angiographic jeopardy score ≤10%. Associations between revascularization status and all-cause death or new myocardial infarction (primary composite endpoint) and all-cause death, new myocardial infarction, or repeat revascularization (secondary composite endpoint) were evaluated. RESULTS: Of the study cohort, 66.0% underwent complete revascularization. Compared with incomplete revascularization, the primary composite endpoint occurred less frequently with complete revascularization (event rate within 5 years 15.4% vs. 22.2%; inverse probability-weighted hazard ratio [IPW-HR]: 0.78; 95% confidence interval [CI]: 0.73 to 0.84; p < 0.0001). The secondary composite endpoint was less likely to occur with complete revascularization (event rate within 5 years 23.3% vs. 37.5%; IPW-HR: 0.61; 95% CI: 0.58 to 0.65; p < 0.0001). Complete revascularization was associated with a reduction in all-cause death (IPW-HR: 0.79; 95% CI: 0.73 to 0.86; p = 0.0004), new myocardial infarction (IPW-HR: 0.76; 95% CI: 0.69 to 0.84; p < 0.0001), and repeat revascularization (IPW-HR: 0.53; 95% CI: 0.49 to 0.57; p < 0.0001). CONCLUSIONS: Results from this large contemporary registry of patients with ACS and PCI for multivessel disease suggest that complete revascularization occurs commonly and is associated with improved clinical outcomes (including survival) within 5 years.

Novel Biomarkers, ST-Elevation Resolution, and Clinical Outcomes Following Primary Percutaneous Coronary Intervention.

Background Despite restoration of epicardial flow following primary percutaneous coronary intervention (PPCI), microvascular reperfusion as reflected by ST-elevation resolution (ST-ER) resolution remains variable and its pathophysiology remains unclear. Methods and Results Using principal component analyses, we explored associations between 91 serum biomarkers drawn before PPCI clustered into 14 pathobiologic processes (including NT-proBNP [N-terminal pro-B-type natriuretic peptide] as an independent cluster), and (1) ST-ER resolution ≥50% versus <50%; and (2) 90-day composite of death, shock, and heart failure. Network analyses were performed to understand interbiomarker relationships between the ST-ER groups. Among the 1160 patients studied, 861 (74%) had ST-ER ≥50% at a median 40 (interquartile range, 23-70) minutes following PPCI, yet both groups had comparable post-PPCI TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow (86.6% versus 82.9%; P=0.25). ST-ER ≥50% was associated with significantly lower pre-PPCI concentrations of platelet activation cluster (particularly P-selectin, von Willebrand factor, and platelet-derived growth factor A) and NT-proBNP, including after risk adjustment. Across both ST-ER groups, strong interbiomarker relationships were noted between pathways indicative of myocardial stretch, platelet activation, and inflammation, whereas with ST-ER <50% correlations between iron homeostasis and inflammation were observed. Of all 14 biomarker clusters, only NT-proBNP was significantly associated with the 90-day clinical composite. Conclusions Suboptimal ST-ER is common despite achieving post-PPCI TIMI grade 3 flow. The cluster of platelet activation proteins and NT-proBNP were strongly correlated with suboptimal ST-ER and NT-proBNP was independently associated with 90-day outcomes. This analysis provides insights into the pathophysiology of microvascular reperfusion in ST-segment-elevation myocardial infarction and suggests novel pre-PPCI risk targets potentially amenable to enhancing tissue-level reperfusion following PPCI.

Circulating troponin and further left ventricular ejection fraction improvement in patients with previously recovered left ventricular ejection fraction.

AIMS: The aim of this study is to determine factors associated with long-term recovery of left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF) and if further recovery also occurs in this group. METHODS AND RESULTS: Among 621 participants enrolled in the Alberta Heart Failure Etiology and Analysis Team (HEART) Study, 316 with Stage C HF underwent comprehensive imaging and biomarker testing at enrolment and at 1-year follow up. Using pre-enrolment data, HF with recovered EF (HFrecEF) was defined as an absolute improvement ≥5% in LVEF from the prior lowest LVEF value, with a final LVEF value > 35% at or prior to study baseline. Participants with all LVEF > 40% were included for comparison. Hospitalization-free survival to 5 years was performed. The median cohort age was 66 years, and time from diagnosis was 4 years; 82% were male patients. Of the 316 patients, 95 (30%) patients had HFrecEF and 56 (18%) patients pHFrEF. On multivariate analysis, only shorter duration of HF was predictive of HFrecEF status. Over 1 year, LVEF increased in the HFrecEF group 4.0% (0.15-7.90, P = 0.042) as compared with persistent HFrEF, who in turn demonstrated higher baseline serum high sensitivity Troponin-T with further increase at follow up 0.55(0.33-0.86, P = 0.011). No change in any parameter in the HFpEF/HFmrEF group at follow up was observed. CONCLUSIONS: Patients with HFrecEF demonstrate evidence of additional late improvement in LVEF and unchanged troponin levels, in contrast to those with persistent HFrEF, where LVEF does not improve and serum troponin rises over time. These data help to inform mechanisms relating to late LV remodelling.

Assessment of Limitations to Optimization of Guideline-Directed Medical Therapy in Heart Failure From the GUIDE-IT Trial: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes. Objective: To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy. Design, Setting, and Participants: GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP-guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019. Main Outcomes and Measures: For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes. Results: Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were "clinically stable" and "already at maximally tolerated therapy." Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of ß-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of ß-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P < .001) and angiotensin receptor blockers (HR, 0.84; 95% CI, 0.71-0.99; P = .04) were associated with reduced risk of all-cause death. Increasing doses of mineralocorticoid antagonists did not appear to be associated with improved outcomes. Conclusions and Relevance: Despite a protocol-driven approach, many patients in GUIDE-IT did not receive medication adjustments and did not achieve optimal GDMT, including those with known elevated NT-proBNP concentrations. These results suggest that opportunities exist to titrate medications for maximal benefit in HF. GUIDE-IT may have failed to achieve treatment benefit because of therapeutic inertia in clinical practice, or current GDMT goals may be unrealistic. Trial Registration: ClinicalTrials.gov Identifier: NCT01685840.

Ambulance use, distance and outcomes in patients with suspected cardiovascular disease: a registry-based geographic information system study.

BACKGROUND: Despite guideline recommendations, the majority of patients with symptoms suggestive of acute coronary syndrome do not use emergency medical services to reach the emergency department (ED). The aim of this study was to investigate the factors associated with EMS utilisation and subsequent patient outcomes. METHODS: Using administrative data, all patients who presented to an ED in the metropolitan areas of Edmonton and Calgary in the years of 2007-2013 with main ED diagnosis of acute coronary syndrome, stable angina or chest pain were included. The travel distance was estimated using the geographic information system method to approximate the distance between the ED and patient home. The clinical endpoints were the 7-day and 30-day all-cause events (death, re-hospitalisation and repeat ED visit). RESULTS: Of 50,881 patients, 30.5% presented by emergency medical services. Patients with older age, female sex, ED diagnosis of acute coronary syndrome, more comorbidities and lower household income were more likely to use emergency medical services to reach the hospital. Longer travel distance was associated with higher emergency medical services use (odds ratio 1.09, 95% confidence interval 1.09-1.10), but it was not a predictor of clinical events. After adjustment for covariates and inverse propensity score weighting, emergency medical services use was associated with a higher risk of 7-day and 30-day clinical events. CONCLUSION: Several demographic and clinical features were associated with higher emergency medical services use including geographical variation. Although longer travel distance was shown to be linked to higher emergency medical services use, it was not an independent predictor of patient outcome. This has implications for the design of emergency medical services systems, triage and early diagnosis and treatment options.

High-throughput targeted proteomics discovery approach and spontaneous reperfusion in ST-segment elevation myocardial infarction.

BACKGROUND: Although spontaneous reperfusion (SR) prior to primary percutaneous coronary intervention (pPCI) is associated with improved outcomes, its pathophysiology remains unclear. The objective of the study was to explore associations between SR in ST-segment elevation myocardial infarction (STEMI) using a multimarker cardiovascular proteins strategy METHODS: We evaluated STEMI patients from the Assessment of Pexelizumab in Acute Myocardial Infarction trial treated with pPCI within 6 hours from symptom onset. SR was core laboratory-defined as pre-PCI Thrombolysis in Myocardial Infarction flow 2 or 3. Ninety-one cardiovascular disease-related serum biomarkers drawn prior to PCI were analyzed using a high-throughput "targeted discovery" panel. Expression levels for individual biomarkers were compared between patients with/without SR. A hierarchical clustering method of biomarkers identified clusters of biomarkers that differentiated the 2 groups. Associations between individual biomarkers and clusters with SR were further evaluated by multivariable logistic regression. RESULTS: Of 683 patients studied, 290 had spontaneous reperfusion; those with compared to without SR were more likely noninferior STEMI and had lower clinical acuity and lower baseline levels of troponin and creatine kinase. SR was associated with a lower occurrence of 90-day composite of death, heart failure, or cardiogenic shock. Fifty-two of 91 individual biomarkers were significantly univariably associated with SR. Forty-five remained significant with adjustment for false discovery rate. Using cluster analysis, 26 biomarkers clusters were identified, explaining 72% of total covariance, and 13 biomarker clusters were significantly associated with SR after multivariable adjustment. SR was associated with higher mean expression levels of proteins in all 13 clusters. The cluster most strongly associated with SR consisted of novel proteins across various distinct, yet interlinked, pathobiological processes (kallikrein-6, matrix extracellular phosphoglycoprotein, matrix mettaloproteinaise-3, and elafin). CONCLUSIONS: Spontaneous reperfusion prior to pPCI in STEMI was associated with a lower risk of adverse clinical events. These exploratory data from a targeted discovery proteomics platform identifies novel proteins across diverse, yet complementary, pathobiological axes that show promise in providing mechanistic insights into spontaneous reperfusion in STEMI. CONDENSED ABSTRACT: Spontaneous reperfusion has been established with improved STEMI outcomes, yet its pathobiology is unclear and appears to involve diverse physiological processes. Using a 91-biomarker high-throughput proteomics platform, we studied 683 STEMI patients in the APEX AMI trial (290 had core laboratory-adjudicated pre-PCI TIMI 2/3 flow) and identified 52 proteins that univariably associate with spontaneous reperfusion. Cluster analysis identified 26 biomarker clusters (explaining 72% of total variance), 13 of which, after multivariable adjustment, were significantly associated with spontaneous reperfusion. Four proteins (kallikrein-6, matrix extracellular phosphoglycoprotein, matrix mettaloproteinaise-3, and elafin) across diverse, yet complementary, pathways appear to be associated most strongly with spontaneous reperfusion.

National trends in coronary intensive care unit admissions, resource utilization, and outcomes.

BACKGROUND: Emerging evidence suggests that coronary intensive care units are evolving into intensive care environments with an increasing burden of non-cardiovascular illness, but previous studies have been limited to older populations or single center experiences. METHODS: Canadian national health-care data was used to identify all patients ≥18 years admitted to dedicated coronary intensive care units (2005-2015) and admissions were categorized as primary cardiac or non-cardiac. The outcomes of interest included longitudinal trends in admission diagnoses, critical care therapies, and all-cause in-hospital mortality. RESULTS: Among the 373,992 patients admitted to a coronary intensive care unit, minimal changes in the proportion of patients admitted with a primary cardiac (88.2% to 86.9%; p<0.001) and non-cardiac diagnoses (11.8% to 13.1%; p<0.001) were observed. Among cardiac admissions, a temporal increase in the proportion of ST-segment elevation myocardial infarction (19.4% to 24.1%, p<0.001), non-ST-segment elevation myocardial infarction (14.6% to 16.2%, p<0.001), heart failure (7.3% to 8.4%, p<0.001), shock (4.9% to 5.7%, p<0.001), and decline in unstable angina (4.9% to 4.0%, p<0.001) and stable coronary diseases (21.3% to 12.4%, p<0.001) was observed. The proportion of patients requiring critical care therapies (57.8% to 63.5%, p<0.001) including mechanical ventilation (9.6% to 13.1%, p<0.001) increased. In-hospital mortality rates for patients with primary cardiac (4.9% to 4.4%; adjusted odds ratio 0.71, 95% confidence interval 0.63-0.79) and non-cardiac (17.8% to 16.1%; adjusted odds ratio 0.84, 0.73-0.97) declined; results were consistent when stratified by academic vs community hospital, and by the presence of on-site percutaneous coronary intervention. CONCLUSION: In a national dataset we observed a changing case-mix among patients admitted to a coronary intensive care unit, though the proportion of patients with a primary cardiac diagnosis remained stable. There was an increase in clinical acuity highlighted by critical care therapies, but in-hospital mortality rates for both primary cardiac and non-cardiac conditions declined across all hospitals. Our findings confirm the changing coronary intensive care unit case-mix and have implications for future coronary intensive care unit training and staffing.