Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study.

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline LDL-C levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

Biologically active adrenomedullin as a marker for residual congestion and early rehospitalization in patients hospitalized for acute heart failure: Data from STRONG-HF.

AIMS: Biologically active adrenomedullin (bio-ADM) is a promising marker of residual congestion. The STRONG-HF trial showed that high-intensity care (HIC) of guideline-directed medical therapy (GDMT) improved congestion and clinical outcomes in heart failure (HF) patients. The association between bio-ADM, decongestion, outcomes and the effect size of HIC of GDMT remains to be elucidated. METHODS AND RESULTS: We measured plasma bio-ADM concentrations in 1005 patients within 2 days prior to anticipated discharge (baseline) and 90 days later. Bio-ADM correlated with most signs of congestion, with the exception of rales. Changes in bio-ADM were strongly correlated with change in congestion status from baseline to day 90 (gamma -0.24; p = 0.0001). Patients in the highest tertile of baseline bio-ADM concentrations were at greater risk than patients in the lowest tertile for the primary outcome of 180-day all-cause mortality or HF rehospitalization (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.42-3.22) and 180-day HF rehospitalization (HR 2.33, 95% CI 1.38-3.94). Areas under the receiver-operating characteristic curves were 0.5977 (95% CI 0.5561-0.6393), 0.5800 (95% CI 0.5356-0.6243), and 0.6159 (95% CI 0.5711-0.6607) for bio-ADM, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their combination, respectively, suggesting that both bio-ADM and NT-proBNP provided similarly modest discrimination for this outcome. A trend towards better discrimination by combined bio-ADM and NT-proBNP than NT-proBNP alone was found (p = 0.059). HIC improved the primary outcome, irrespective of baseline bio-ADM concentration (interaction p = 0.37). In contrast to NT-proBNP, the 90-day change in bio-ADM did not differ significantly between HIC and usual care. CONCLUSIONS: Bio-ADM is a marker of congestion and predicts congestion at 3 months after a HF hospitalization. Higher bio-ADM was modestly associated with a higher risk of death and early hospital readmission and may have added value when combined with NT-proBNP.

Characteristics, treatment, and outcomes of early vs. late enrollees of the STRONG-HF trial.

BACKGROUND: The STRONG-HF trial showed that high-intensity care (HIC) consisting of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up reduced all-cause death or heart failure (HF) readmission at 180 days compared to usual care (UC). We hypothesized that significant differences in patient characteristics, management, and outcomes over the enrolment period may exist. METHODS: Two groups of the 1,078 patients enrolled in STRONG-HF were created according to the order of enrolment within center. The early group consisted of the first 10 patients enrolled at each center (N = 342) and the late group consisted of the following patients (N = 736). RESULTS: Late enrollees were younger, had more frequently reduced ejection fraction, slightly lower NT-proBNP and creatinine levels compared with early enrollees. The primary outcome occurred less frequently in early compared to late enrollees (15% vs. 21%, aHR 0.65, 95% CI 0.42-0.99, P = .044). No treatment-by-enrolment interaction was seen in respect to the average percentage of optimal dose of GDMT after randomization, which was consistently higher in early and late patients randomized to HIC compared to UC. The higher use of renin-angiotensin-inhibitors in the HIC arm was more pronounced in the late enrollees both after randomization (interaction-P = .013) and at 90 days (interaction-P < .001). No interaction was observed for safety events. Patients randomized late to UC displayed a trend toward more severe outcomes (26% vs. 16%, P = .10), but the efficacy of HIC showed no interaction with the enrolment group (aHR 0.77, 95% CI 0.35-1.67 in early and 0.58, 95% CI 0.40-0.83 in late enrollees, adjusted interaction-P = .51) with similar outcomes in the HIC arm in late and early enrollees (16% vs. 13%, P = .73). CONCLUSIONS: Late enrollees have different clinical characteristics and higher event rates compared to early enrollees. GDMT implementation in the HIC arm robustly achieved similar doses with consistent efficacy in early and late enrollees, mitigating the higher risk of adverse outcome in late enrollees. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03412201.

Titration of Medications After Acute Heart Failure Is Safe, Tolerated, and Effective Regardless of Risk.

BACKGROUND: Guideline-directed medical therapy (GDMT) decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF (Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure), high-intensity care (HIC) in the form of rapid uptitration of heart failure (HF) GDMT was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses. OBJECTIVES: The authors sought to assess safety, tolerability, and efficacy of HIC according to the simple, powerful, and clinically translatable MAGGIC (Meta-Analysis Global Group in Chronic) HF risk score. METHODS: In STRONG-HF, 1,078 patients with acute HF were randomized to HIC (uptitration of treatments to 100% of recommended doses within 2 weeks of discharge and 4 scheduled outpatient visits over the 2 months after discharge) vs usual care (UC). The primary endpoint was the composite of all-cause death or first HF rehospitalization at day 180. Baseline HF risk profile was determined by the previously validated MAGGIC risk score. Treatment effect was stratified according to MAGGIC risk score both as a categorical and continuous variable. RESULTS: Among 1,062 patients (98.5%) with complete data for whom a MAGGIC score could be calculated at baseline, GDMT use at baseline was similar across MAGGIC tertiles. Overall GDMT prescriptions achieved for individual medication classes were higher in the HIC vs UC group and did not differ by MAGGIC risk score tertiles (interaction nonsignificant). The incidence of all-cause death or HF readmission at day 180 was, respectively, 16.3%, 18.9%, and 23.2% for MAGGIC risk score tertiles 1, 2, and 3. The HIC arm was at lower risk of all-cause death or HF readmission at day 180 (HR: 0.66; 95% CI: 0.50-0.86) and this finding was robust across MAGGIC risk score modeled as a categorical (HR: 0.51; 95% CI: 0.62-0.68 in tertiles 1, 2, and 3; interaction nonsignificant) for all comparisons and continuous (interaction nonsignificant) variable. The rate of adverse events was higher in the HIC group, but this observation did not differ based on MAGGIC risk score tertile (interaction nonsignificant). CONCLUSIONS: HIC led to better use of GDMT and lower HF-related morbidity and mortality compared with UC, regardless of the underlying HF risk profile. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies [STRONG-HF]; NCT03412201).

Safety Of The Pcsk9 Inhibitor Alirocumab: insights From 47,296 Patient-Years Of Observation.

The ODYSSEY OUTCOMES trial, comprising over 47 000 patient-years of placebo-controlled observation, demonstrated important reductions in the risk of recurrent ischaemic cardiovascular events with the monoclonal antibody to proprotein convertase subtilisin/kexin type 9 alirocumab, as well as lower all-cause death. These benefits were observed in the context of substantial and persistent lowering of low-density lipoprotein cholesterol with alirocumab compared to that achieved with placebo. The safety profile of alirocumab was indistinguishable from matching placebo except for a ∼1.7% absolute increase in local injection-site reactions. Further, the safety of alirocumab compared to placebo was evident in vulnerable groups identified before randomization, such as the elderly and those with diabetes mellitus, previous ischaemic stroke, or chronic kidney disease. The frequency of adverse events and laboratory-based abnormalities was generally similar to that in placebo-treated patients. Thus, alirocumab appears to be a safe and effective lipid-modifying treatment over a duration of at least 5 years.

Impact of Rapid Up-Titration of Guideline-Directed Medical Therapies on Quality of Life: Insights From the STRONG-HF Trial.

BACKGROUND: This analysis provides details on baseline and changes in quality of life (QoL) and its components as measured by EQ-5D-5L questionnaire, as well as association with objective outcomes, applying high-intensity heart failure (HF) care in patients with acute HF. METHODS: In STRONG-HF trial (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) patients with acute HF were randomized just before discharge to either usual care or a high-intensity care strategy of guideline-directed medical therapy up-titration. Patients ranked their state of health on the EQ-5D visual analog scale score ranging from 0 (the worst imaginable health) to 100 (the best imaginable health) at baseline and at 90 days follow-up. RESULTS: In 1072 patients with acute HF with available assessment of QoL (539/533 patients assigned high-intensity care/usual care) the mean baseline EQ-visual analog scale score was 59.2 (SD, 15.1) with no difference between the treatment groups. Patients with lower baseline EQ-visual analog scale (meaning worse QoL) were more likely to be women, self-reported Black and non-European (P<0.001). The strongest independent predictors of a greater improvement in QoL were younger age (P<0.001), no HF hospitalization in the previous year (P<0.001), lower NYHA class before hospital admission (P<0.001) and high-intensity care treatment (mean difference, 4.2 [95% CI, 2.5-5.8]; P<0.001). No statistically significant heterogeneity in the benefits of high-intensity care was seen across patient subgroups of different ages, with left ventricular ejection fraction above or below 40%, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and systolic blood pressure above or below the median value. The treatment effect on the primary end point did not vary significantly across baseline EQ-visual analog scale (Pinteraction=0.87). CONCLUSIONS: Early up-titration of guideline-directed medical therapy significantly improves all dimensions of QoL in patients with HF and improves prognosis regardless of baseline self-assessed health status. The likelihood of achieving optimal doses of HF medications does not depend on baseline QoL. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03412201.

Blood pressure and intensive treatment up-titration after acute heart failure hospitalization: Insights from the STRONG-HF trial.

AIMS: A high-intensity care (HIC) strategy with rapid guideline-directed medical therapy (GDMT) up-titration and close follow-up visits improved outcomes, compared to usual care (UC), in patients recently hospitalized for acute heart failure (AHF). Hypotension is a major limitation to GDMT implementation. We aimed to assess the impact of baseline systolic blood pressure (SBP) on the effects of HIC versus UC and the role of early SBP changes in STRONG-HF. METHODS AND RESULTS: A total of 1075 patients hospitalized for AHF with SBP ≥100 mmHg were included in STRONG-HF. For the purpose of this post-hoc analysis, patients were stratified by tertiles of baseline SBP (<118, 118-128, and ≥129 mmHg) and, in the HIC arm, by tertiles of changes in SBP from the values measured before discharge to those measured at 1 week after discharge (≥2 mmHg increase, ≤7 mmHg decrease to <2 mmHg increase, and ≥8 mmHg decrease). The primary endpoint was 180-day heart failure rehospitalization or death. The effect of HIC versus UC on the primary endpoint was independent of baseline SBP evaluated as tertiles (pinteraction = 0.77) or as a continuous variable (pinteraction = 0.91). In the HIC arm, patients with increased, stable and decreased SBP at 1 week reached 83.5%, 76.2% and 75.3% of target doses of GDMT at day 90. The risk of the primary endpoint was not significantly different between patients with different SBP changes at 1 week (adjusted p = 0.46). CONCLUSIONS: In STRONG-HF, the benefits of HIC versus UC were independent of baseline SBP. Rapid GDMT up-titration was performed also in patients with an early SBP drop, resulting in similar 180-day outcome as compared to patients with stable or increased SBP.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Tricuspid Regurgitation and Clinical Outcomes in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Tricuspid regurgitation (TR) is common and is associated with poor outcomes in patients with heart failure (HF). However, data with adjudicated events from fully characterized patients with heart failure with reduced ejection fraction (HFrEF) are lacking. OBJECTIVES: This study sought to explore the association between mild or moderate/severe TR and clinical outcomes of patients with HFrEF. METHODS: GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) was a double-blind, placebo-controlled randomized trial comparing omecamtiv mecarbil vs placebo in patients with symptomatic HFrEF. RESULTS: Among the 8,232 patients analyzed in the GALACTIC-HF trial, 8,180 (99%) had data regarding baseline TR (none: n = 6,476 [79%], mild: n = 919 [11%], and moderate/severe: n = 785 [10%]). The primary composite outcome of a first HF event or cardiovascular death occurred in 2,368 (36.6%) patients with no TR, 353 (38.4%) patients with mild TR, and 389 (49.6%) patients with moderate/severe TR. Moderate/severe TR was independently associated with a higher relative risk of the primary composite outcome compared with either no TR (adjusted HR: 1.12 [95% CI: 1.01-1.26]; P = 0.046) or no/mild TR (adjusted HR: 1.14 [95% CI: 1.02-1.27]; P = 0.025) driven predominantly by HF events. The association between moderate/severe TR and clinical outcomes was more pronounced in outpatients with worse renal function, higher left ventricular ejection fraction, and lower N-terminal pro-B-type natriuretic peptide and bilirubin levels. The beneficial treatment effect of omecamtiv mecarbil vs placebo on clinical outcomes was not modified by TR. CONCLUSIONS: In symptomatic patients with HFrEF, baseline moderate/severe TR was independently associated with cardiovascular death or HF events driven predominantly by HF events. The beneficial treatment effect of omecamtiv mecarbil on the primary outcome was not modified by TR.

Cardiac Troponin and Treatment Effects of Omecamtiv Mecarbil: Results From the GALACTIC-HF Study.

BACKGROUND: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329). METHODS: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil. RESULTS: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2). CONCLUSIONS: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI.

Low-Dose Colchicine in Patients With Type 2 Diabetes and Recent Myocardial Infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

OBJECTIVE: The cardiovascular benefits of low-dose colchicine have been demonstrated in patients with coronary disease. Its effects were evaluated in this prespecified analysis in patients with type 2 diabetes (T2D) from the Colchicine Cardiovascular Outcomes Trial (COLCOT). RESEARCH DESIGN AND METHODS: COLCOT was a randomized, double-blinded trial of colchicine, 0.5 mg daily, versus placebo initiated within 30 days after a myocardial infarction. RESULTS: There were 959 patients with T2D enrolled and monitored for a median of 22.6 months. A primary end point event occurred in 8.7% of patients in the colchicine group and in 13.1% in the placebo group (hazard ratio 0.65; 95% CI 0.44-0.96; P = 0.03). Nausea was reported in 2.7% and 0.8% in the study groups (P = 0.03), and pneumonia occurred in 2.4% and 0.4% (P = 0.008). CONCLUSIONS: Among patients with T2D and a recent myocardial infarction, colchicine, 0.5 mg daily, leads to a large reduction of cardiovascular events. These results support the conduct of the COLCOT-T2D trial in primary prevention.

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Safety Indicators in Patients Receiving High-intensity Care After Hospital Admission for Acute Heart Failure: The STRONG-HF Trial.

BACKGROUND: Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) demonstrated the safety and efficacy of rapid up-titration of guideline-directed medical therapy (GDMT) with high-intensity care (HIC) compared with usual care in patients hospitalized for acute heart failure (HF). In the HIC group, the following safety indicators were used to guide up-titration: estimated glomerular filtration rate of <30 mL/min/1.73 m2, serum potassium of >5.0 mmol/L, systolic blood pressure (SBP) of <95 mmHg, heart rate of <55 bpm, and N-terminal pro-B-type natriuretic peptide concentration of >10% higher than predischarge values. METHODS AND RESULTS: We examined the impact of protocol-specified safety indicators on achieved dose of GDMT and clinical outcomes. Three hundred thirteen of the 542 patients in the HIC arm (57.7%) met ≥1 safety indicator at any follow-up visit 1-6 weeks after discharge. As compared with those without, patients meeting ≥1 safety indicator had more severe HF symptoms, lower SBP, and higher heart rate at baseline and achieved a lower average percentage of GDMT optimal doses (mean difference vs the HIC arm patients not reaching any safety indicator, -11.0% [95% confidence interval [CI] -13.6 to -8.4%], P < .001). The primary end point of 180-day all-cause death or HF readmission occurred in 15.0% of patients with any safety indicator vs 14.2% of those without (adjusted hazard ratio 0.84, 95% CI 0.48-1.46, P = .540). None of each of the safety indicators, considered alone, was significantly associated with the primary end point, but an SBP of <95 mm Hg was associated with a trend toward increased 180-day all-cause mortality (adjusted hazard ratio 2.68, 95% CI 0.94-7.64, P = .065) and estimated glomerular filtration rate decreased to <30 mL/min/1.73 m2 with more HF readmissions (adjusted hazard ratio 3.60, 95% CI 1.22-10.60, P = .0203). The occurrence of a safety indicator was associated with a smaller 90-day improvement in the EURO-QoL 5-Dimension visual analog scale (adjusted mean difference -3.32 points, 95% CI -5.97 to -0.66, P = .015). CONCLUSIONS: Among patients with acute HF enrolled in STRONG-HF in the HIC arm, the occurrence of any safety indicator was associated with the administration of slightly lower GDMT doses and less improvement in quality of life, but with no significant increase in the primary outcome of 180-day HF readmission or death when appropriately addressed according to the study protocol.

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

Optimization of Evidence-Based Heart Failure Medications After an Acute Heart Failure Admission: A Secondary Analysis of the STRONG-HF Randomized Clinical Trial.

Importance: The Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies (STRONG-HF) trial strived for rapid uptitration aiming to reach 100% optimal doses of guideline-directed medical therapy (GDMT) within 2 weeks after discharge from an acute heart failure (AHF) admission. Objective: To assess the association between degree of GDMT doses achieved in high-intensity care and outcomes. Design, Setting, and Participants: This was a post hoc secondary analysis of the STRONG-HF randomized clinical trial, conducted from May 2018 to September 2022. Included in the study were patients with AHF who were not treated with optimal doses of GDMT before and after discharge from an AHF admission. Data were analyzed from January to October 2023. Interventions: The mean percentage of the doses of 3 classes of HF medications (renin-angiotensin system inhibitors, ß-blockers, and mineralocorticoid receptor antagonists) relative to their optimal doses was computed. Patients were classified into 3 dose categories: low (<50%), medium (≥50% to <90%), and high (≥90%). Dose and dose group were included as a time-dependent covariate in Cox regression models, which were used to test whether outcomes differed by dose. Main Outcome Measures: Post hoc secondary analyses of postdischarge 180-day HF readmission or death and 90-day change in quality of life. Results: A total of 515 patients (mean [SD] age, 62.7 [13.4] years; 311 male [60.4%]) assigned high-intensity care were included in this analysis. At 2 weeks, 39 patients (7.6%) achieved low doses, 254 patients (49.3%) achieved medium doses, and 222 patients (43.1%) achieved high doses. Patients with lower blood pressure and more congestion were less likely to be uptitrated to optimal GDMT doses at week 2. As a continuous time-dependent covariate, an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day HF readmission or all-cause death (primary end point: adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81-0.98; P = .01) and a decrease in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; P = .007). Quality of life at 90 days, measured by the EQ-5D visual analog scale, improved more in patients treated with higher doses of GDMT (mean difference, 0.10; 95% CI, -4.88 to 5.07 and 3.13; 95% CI, -1.98 to 8.24 points in the medium- and high-dose groups relative to the low-dose group, respectively; P = .07). Adverse events to day 90 occurred less frequently in participants with HIC who were prescribed higher GDMT doses at week 2. Conclusions and Relevance: Results of this post hoc analysis of the STRONG-HF randomized clinical trial show that, among patients randomly assigned to high-intensity care, achieving higher doses of HF GDMT 2 weeks after discharge was feasible and safe in most patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03412201.

Rationale and design of the effect of evolocumab in patients at high cardiovascular risk without prior myocardial infarction or stroke (VESALIUS-CV) trial.

BACKGROUND: The reduction of low-density lipoprotein cholesterol (LDL-C) with evolocumab, a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9i), reduces the risk of major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD) with a prior MI, prior stroke, or symptomatic peripheral artery disease, with no offsetting safety concerns. The effect of evolocumab on CV outcomes in lower risk patients without a history of MI or stroke has not been explored. STUDY DESIGN: VESALIUS-CV is a randomized, double-blind, placebo-controlled, global clinical trial designed to evaluate the effect of evolocumab on the risk of major cardiovascular events in patients at high cardiovascular risk but without a prior ischemic event. The study population consists of 12,301 patients with atherosclerosis or high-risk diabetes mellitus without a prior MI or stroke; an LDL-C ≥ 90 mg/dL, or non-high-density lipoprotein cholesterol (non-HDL-C) ≥ 120 mg/dL, or apolipoprotein B ≥ 80 mg/dL; and treated with optimized lipid-lowering therapy. Patients were randomized in a 1:1 ratio to evolocumab 140 mg subcutaneously every 2 weeks or matching placebo. The primary efficacy objective is to assess whether evolocumab reduces the risk of the dual primary composite endpoints of coronary heart disease (CHD) death, myocardial infarction (MI), or ischemic stroke (triple primary endpoint) and of CHD death, MI, ischemic stroke, or ischemia-driven arterial revascularization (quadruple primary endpoint). Recruitment began in June 2019 and completed in November 2021. The trial is planned to continue until at least 751 patients experience an adjudicated triple endpoint, at least 1254 experience an adjudicated quadruple endpoint, and the median follow-up is ≥4.5 years. CONCLUSION: VESALIUS-CV will determine whether the addition of evolocumab to optimized lipid-lowering therapy reduces cardiovascular events in patients at high cardiovascular risk without a prior MI or stroke. TRIAL REGISTRATION: NCT03872401.

Maculopatía paracentral aguda media y neurorretinopatía macular aguda / Paracentral Acute Middle Maculopathy and Acute Macular Neuroretinopathy

La neurorretinopatía macular aguda es una condición rara con patogenia microvascular. Se presenta con un inicio agudo con escotomas paracentrales correspondientes a lesiones paramaculares evidentes. Los avances en las imágenes multimodales permitieron caracterizar este trastorno de retina y crear nuevos conceptos. Serraf, en el 2013, identificó dos formas por medio de la tomografía de coherencia óptica dominio espectral: el tipo 1 conocido como maculopatía paracentral aguda media en la cual se observa una banda hiperreflectiva en la capa nuclear interna, y el tipo 2 en el cual la banda hiperreflectiva se ubica en la capa nuclear externa, que involucra la zona elipsoide y la zona de interdigitación con el epitelio pigmentario de la retina. Hasta el momento no existe cura; pero se puede actuar sobre los factores de riesgo. Por ser una condición rara y por no existir reportes hasta el momento en Cuba es que se presentan a continuación dos pacientes con cuadros clínicos similares de estas dos variantes; concluyendo la importancia que presentan las imágenes multimodales como medio auxiliar diagnóstico(AU)

Acute macular neuroretinopathy is a rare condition with complex pathogenesis and microvascular cause. It appears with acute onset, with paracentral scotomas corresponding to obvious paramacular lesions. Advances in multimodal imaging made it possible to characterize this retinal disorder and to create new concepts. Serraf, in 2013, identified two forms by spectral domain optical coherence tomography: type 1, known as paracentral acute middle maculopathy, in which a hyperreflective band is observed in the inner nuclear layer; and type 2, in which the hyperreflective band is located in the outer nuclear layer, involving the ellipsoid zone and the zone of interdigitation with the retinal pigment epithelium. Up to this moment, there is no cure; but it is possible to act on the risk factors. Because it is a rare condition and because there are no reports so far in Cuba, two patients with similar clinical pictures of these two variants are presented; concluding the importance of multimodal images as an auxiliary diagnostic tool(AU)

Butter from Different Species: Composition and Quality Parameters of Products Commercialized in the South of Spain.

Butter is an important product for the dairy industry due to its particular sensory attributes and nutritional value, while the variability of the composition of the fatty acids in the milk can alter the nutritional and physical properties of butter and its acceptance by consumers. Butter is highly appreciated for its distinctive flavor and aroma; however, one of its main drawbacks lies in the difficulty in spreading it at low temperatures. Several types of butter that are present in the market were used in this study. We assessed the variability in the composition of the samples regarding their texture, color properties, and volatile organic compound profiles. We analyzed samples commercially produced from sheep's milk (SB), goat's milk (GB), and cow's milk (CB); samples from the latter species with (CSB) and without salt (CB); and the low-fat (CLB) version. All the physicochemical composition parameters were significantly affected by the effect of the type of butter, although only 29 out of the 45 fatty acids examined were identified in the butter samples analyzed. The textural properties of the butters were influenced by both their solid fat content and the fatty acid profile. In addition, the origin of the milk not only affected the texture parameters but also the color of the butters and the compounds associated with traits such as odor and flavor. Through the multivariate data analysis of butter fatty acids and volatile compound percentages, we observed a clear differentiation of the samples based on the species of origin.

Sex Differences in Heart Failure With Reduced Ejection Fraction in the GALACTIC-HF Trial.

BACKGROUND: Women with heart failure with reduced ejection fraction (HFrEF) receive less guideline-recommended therapy and experience worse quality of life than men. OBJECTIVES: The authors sought to assess differences in baseline characteristics, outcomes, efficacy, and safety of omecamtiv mecarbil between men and women enrolled in the GALACTIC-HF (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction) study. METHODS: In GALACTIC-HF, patients with symptomatic heart failure with EF of 35% or less, recent heart failure event, and elevated natriuretic peptides were randomized to omecamtiv mecarbil or placebo. The current analysis investigated differences in baseline characteristics, clinical outcomes, and efficacy and safety of omecamtiv mecarbil between men and women. RESULTS: Of 8,232 patients analyzed, 21.2% were women. Women more likely self-identified as being Black, had worse symptoms (lower Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and were less likely to be treated with angiotensin receptor/neprilysin inhibitor and devices at baseline. Compared with men, women had lower rates of the primary endpoint (adjusted HR: 0.80, 95% CI: 0.73-0.88). Sex did not significantly modify omecamtiv mecarbil's treatment effect (P interaction = 0.68). Women also had 20% less risk of cardiovascular death, heart failure event, and all-cause death. Women participants had lower rates of serious adverse events. CONCLUSIONS: Women participants of the GALACTIC-HF trial had worse quality of life and were less likely to be treated with guideline-based therapies at baseline. Despite KCCQ-TSS being predictive of poor outcomes in this population, women had a 20% lower risk of an HF event or cardiovascular death compared with men. The beneficial effect of omecamtiv mecarbil did not significantly differ by sex. (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).