Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have ...been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated.
The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF<45%), and at least 1 additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite end point is time to first hospitalization for HF or all-cause mortality.
EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high-risk for the development of future HF and mortality.
This study sought to evaluate the incidence, the predictors, and the associations with outcomes of changes in ejection fraction (EF) in heart failure (HF) patients.
EF determines therapy in HF, but ...information is scarce about incidence, determinants, and prognostic implications of EF change over time.
Patients with ≥2 EF measurements registered in the Swedish Heart Failure Registry were categorized as heart failure with preserved ejection fraction (HFpEF) (EF ≥50%), heart failure with midrange ejection fraction (HFmrEF) (EF 40% to 49%), or heart failure with reduced ejection fraction (HFrEF) (EF <40%). Changes among categories were recorded, and associations among EF changes, predictors, and all-cause mortality and/or HF hospitalizations were analyzed using logistic and Cox regressions.
Of 4,942 patients at baseline, 18% had HFpEF, 19% had HFmrEF, and 63% had HFrEF. During follow-up, 21% and 18% of HFpEF patients transitioned to HFmrEF and HFrEF, respectively; 37% and 25% of HFmrEF patients transitioned to HFrEF and HFpEF, respectively; and 16% and 10% of HFrEF patients transitioned to HFmrEF and HFpEF, respectively. Predictors of increased EF included female sex, cases of less severe HF, and comorbidities. Predictors of decreased EF included diabetes, ischemic heart disease, and cases of more severe HF. Use of renin-angiotensin-system inhibitors was associated with lower likelihood of EF increase, but not with EF decrease (i.e., stable EF). Increased EF was associated with a lower risk (hazard ratio HR: 0.62; 95% confidence interval CI: 0.55 to 0.69) and decreased EF with a higher risk (HR: 1.15; 95% CI: 1.01 to 1.30) of mortality and/or HF hospitalizations. Prognostic implications were most evident for transitions to and from HFrEF.
Increases in EF occurred in one-fourth of HFrEF and HFmrEF patients, and decreases occurred in more than one-third of patients with HFpEF and HFmrEF. EF change was associated with a wide range of important clinical and organizational factors as well as with outcomes, particularly transitions to and from HFrEF.
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The relationship between the benefits of empagliflozin in heart failure with reduced ejection fraction (HFrEF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) has not been reported.
The ...authors sought to evaluate the relationship between NT-proBNP and empagliflozin effects in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Patients with HFrEF were randomly assigned to placebo or empagliflozin 10 mg daily. NT-proBNP was measured at baseline, 4 weeks, 12 weeks, 52 weeks, and 100 weeks. Patients were divided into quartiles of baseline NT-proBNP.
Incidence rates for each study outcome were 4- to 6-fold higher among those in the highest versus lowest NT-proBNP quartiles (≥3,480 vs <1,115 pg/mL). Study participants with higher NT-proBNP had 2- to 3-fold total hospitalizations higher than the lowest NT-proBNP quartile. Empagliflozin reduced risk for major cardiorenal events without heterogeneity across NT-proBNP quartiles (primary endpoint P
= 0.94; renal composite endpoint P
= 0.71). Empagliflozin treatment significantly reduced NT-proBNP at all timepoints examined; by 52 weeks, the adjusted mean difference from placebo was 13% (P < 0.001). An NT-proBNP in the lowest quartile (<1,115 pg/mL) 12 weeks after randomization was associated with lower risk for subsequent cardiovascular death or heart failure hospitalization regardless of baseline concentration. Treatment with empagliflozin resulted in 27% higher adjusted odds of an NT-proBNP concentration of <1,115 pg/mL by 12 weeks compared with placebo (P = 0.01).
In EMPEROR-Reduced, higher baseline NT-proBNP concentrations were associated with greater risk for adverse heart failure or renal outcomes, but empagliflozin reduced risk regardless of baseline NT-proBNP concentration. The NT-proBNP concentration after treatment with empagliflozin better informs subsequent prognosis than pretreatment concentrations. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction EMPEROR-Reduced; NCT03057977).
Abstract
Aims
Hypoglycaemia, in patients with Type 2 diabetes (T2D) is associated with an increased risk for cardiovascular (CV) events. In EMPA-REG OUTCOME, the sodium-glucose co-transporter-2 ...inhibitor empagliflozin reduced the risk of CV death by 38% and heart failure hospitalization (HHF) by 35%, while decreasing glycated haemoglobin (HbA1c) without increasing hypoglycaemia. We investigated CV outcomes in patients with hypoglycaemia during the trial and the impact of hypoglycaemia on the treatment effect of empagliflozin.
Methods and results
About 7020 patients with T2D (HbA1c 7–10%) were treated with empagliflozin 10 or 25 mg, or placebo and followed for median 3.1 years. The relationship between on-trial hypoglycaemia and CV outcomes, and effects of empagliflozin on outcomes by incident hypoglycaemia HYPO-broad: symptomatic hypoglycaemia with plasma glucose (PG) ≤70 mg/dL, any hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia, and HYPO-strict: hypoglycaemia with PG <54 mg/dL, or severe hypoglycaemia was investigated using adjusted Cox regression models with time-varying covariates for hypoglycaemia and interaction with treatment. HYPO-broad occurred in 28% in each group and HYPO-strict in 19%. In the placebo group, hypoglycaemia was associated with an increased risk of HHF for both HYPO-broad hazard ratio (HR, 95% confidence interval, CI) 1.91 (1.25–2.93) and HYPO-strict 1.72 (1.06–2.78). HYPO-broad (but not HYPO-strict) was associated with an increased risk of myocardial infarction (MI) HR 1.56 (1.06–2.29). Empagliflozin improved CV outcomes, regardless of occurrence of hypoglycaemia (P-for interactions >0.05).
Conclusion
In this post hoc exploratory analysis, hypoglycaemia was associated with an increased risk of HHF and MI. Hypoglycaemia risk was not increased with empagliflozin and incident hypoglycaemia did not attenuate its cardio-protective effects.
This dual-site study evaluated the diagnostic accuracy of the method.
Pittsburgh compound (11CPIB) positron emission tomography (PIB-PET) has shown promise as a specific and noninvasive method for ...the diagnosis of cardiac amyloidosis (CA).
The study had 2 parts. In the initial study, 51 subjects were included, 36 patients with known CA and increased wall thickness (15 immunoglobulin light chain AL and 21 transthyretin ATTR amyloidosis) and 15 control patients (7 were nonamyloid hypertrophic and 8 healthy volunteers). Subjects underwent PIB-PET and echocardiography. Sensitivity and specificity of PIB-PET were established for 2 simple semiquantitative approaches, standardized uptake value ratio (SUVR) and retention index (RI). The second part of the study included 11 amyloidosis patients (5 AL and 6 hereditary ATTR) without increased wall thickness to which the optimal cutoff values of SUVR (>1.09) and RI (>0.037 min-1) were applied prospectively.
The diagnostic accuracy of visual inspection of 11CPIB uptake was 100% in discriminating CA patients with increased wall thickness from controls. Semiquantitative 11CPIB uptake discriminated CA from controls with a 94% (95% confidence interval CI: 80% to 99%) sensitivity for both SUVR and RI and specificity of 93% (95% CI: 66% to 100%) for SUVR and 100% (95% CI: 75% to 100%) for RI. 11CPIB uptake was significantly higher in AL-CA than in ATTR-CA patients (p < 0.001) and discriminated AL-CA from controls with 100% (95% CI: 88% to 100%) accuracy for both the semiquantitative measures. In the prospective group without increased wall thickness, RI was elevated compared to controls (p = 0.001) and 5 of 11 subjects were evaluated as 11CPIB PET positive.
In a dual-center setting, 11CPIB PET was highly accurate in detecting cardiac involvement in the main amyloid subtypes, with 100% accuracy in AL amyloidosis. A proportion of amyloidosis patients without known cardiac involvement were 11CPIB PET positive, indicating that the method may detect early stages of CA.
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Comorbidities may differently affect treatment response and cause-specific outcomes in heart failure (HF) with preserved (HFpEF) vs. mid-range/mildly-reduced (HFmrEF) vs. reduced (HFrEF) ejection ...fraction (EF), complicating trial design. In patients with HF, we performed a comprehensive analysis of type 2 diabetes (T2DM), atrial fibrillation (AF) chronic kidney disease (CKD), and cause-specific outcomes.
Of 42,583 patients from the Swedish HF registry (23% HFpEF, 21% HFmrEF, 56% HFrEF), 24% had T2DM, 51% CKD, 56% AF, and 8% all three comorbidities. HFpEF had higher prevalence of CKD and AF, HFmrEF had intermediate prevalence of AF, and prevalence of T2DM was similar across the EF spectrum. Patients with T2DM, AF and/or CKD were more likely to have also other comorbidities and more severe HF. Risk of cardiovascular (CV) events was highest in HFrEF vs. HFpEF and HFmrEF; non-CV risk was highest in HFpEF vs. HFmrEF vs. HFrEF. T2DM increased CV and non-CV events similarly but less so in HFpEF. CKD increased CV events somewhat more than non-CV events and less so in HFpEF. AF increased CV events considerably more than non-CV events and more so in HFpEF and HFmrEF.
HFpEF is distinguished from HFmrEF and HFrEF by more comorbidities, non-CV events, but lower effect of T2DM and CKD on events. CV events are most frequent in HFrEF. To enrich for CV vs. non-CV events, trialists should not exclude patients with lower EF, AF and/or CKD, who report higher CV risk.
•Of 42,583 HF patients, 24% had T2DM, 51% CKD, 56% AF, and 8% all three comorbidities.•HFpEF was distinguished from HFmrEF and HFrEF by more comorbidities and non-CV events.•HFpEF was characterized by lower effect of T2DM and CKD on events.•CV events were most frequent in HFrEF.•To enrich for CV vs. non-CV events, trialists should choose lower EF, more AF, and more CKD.
Abstract Background The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized. Methods This study comprised ...prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease mostly atherosclerotic (ASCVD) were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply–demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type. Results There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620–0.998), P = 0.0486, largely driven by its effect on type 1 rate ratio, 0.79 (95% CI, 0.61–1.04) and type 2 MIs rate ratio, 0.67 (95% CI, 0.41–1.10). Conclusions In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2. Trail Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01131676.
Acute coronary syndrome (ACS) is frequently complicated by evidence of heart failure (HF). Those at highest risk for acute decompensated HF in the setting of ACS (ACS-HF) are older, female, and have ...preexisting heart disease, type 2 diabetes mellitus, hypertension, and/or kidney disease. The presence of ACS-HF is strongly associated with higher mortality and more frequent readmissions, especially for HF. Low implementation of guideline-directed medical therapy has further complicated the clinical care of this high-risk population. Improved utilization of current therapies, coupled with further investigation of strategies to manage ACS-HF, is desperately needed to improve outcomes in this vulnerable population, and the results of currently ongoing or recently concluded ACS-HF studies in this population are of great interest. In this review, we explore the pathophysiology, epidemiology, risk factors, and outcomes for patients with ACS-HF, and describe both existing evidence for management of this challenging condition and areas requiring further research.
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•Acute decompensated heart failure in the setting of ACS is widely prevalent and associated with increased risk of both short- and long-term morbidity and mortality•Recent neutral findings for use of ARNI after MI underscore the need for dedicated trials exploring the efficacy of new GDMT therapies in the post-MI population•Future work is needed to improve implementation of existing therapies, and to identify new therapies for this high-risk group
Background In cardiovascular outcome trials, the sodium glucose cotransporter 2 inhibitor empagliflozin and glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide caused similar reductions in ...major adverse cardiac events (MACE). We compared clinical outcomes in routine clinical care. Methods and Results EMPLACE (Cardiovascular and Renal Outcomes, and Mortality in Danish Patients with Type 2 Diabetes Who Initiate Empagliflozin Versus GLP‐1RA: A Danish Nationwide Comparative Effectiveness Study) is an ongoing nationwide population‐based comparative effectiveness cohort study in Denmark. For the present study, we included 14 498 new users of empagliflozin and 12 706 new users of liraglutide, 2015 to 2018. Co‐primary outcomes were expanded major adverse cardiac events (stroke, myocardial infarction, unstable angina, coronary revascularization, hospitalization for heart failure HHF, or all‐cause death); HHF or all‐cause death; and first HHF or first initiation of loop‐diuretic therapy. Secondary outcomes included all‐cause hospitalization or death. We applied propensity score balancing and Cox regression to compute adjusted hazard ratios (aHRs) in on‐treatment (OT) and intention‐to‐treat (ITT) analyses. Cohorts were well balanced at baseline (median age 61 years, 59% men, diabetes mellitus duration 6.6 years, 30% with preexisting cardiovascular disease). During mean follow‐up of 1.1 years in OT and 1.5 years in ITT analyses, empagliflozin versus liraglutide was associated with a similar rate of expanded major adverse cardiac events (OT aHR, 1.02; 95% CI, 0.91–1.14; ITT aHR, 1.06; 95% CI, 0.96–1.17), and HHF or all‐cause death (OT aHR, 0.97; 95% CI, 0.85–1.11; ITT aHR, 1.02; 95% CI, 0.91–1.14); and a decreased rate of a first incident HHF or loop‐diuretic initiation (OT aHR, 0.80; 95% CI, 0.68–0.94; ITT aHR, 0.87; 95% CI, 0.76–1.00), and of all‐cause hospitalization or death (OT aHR, 0.93; 95% CI, 0.89–0.98; ITT aHR, 0.93; 95% CI, 0.90–0.97). Conclusions Empagliflozin and liraglutide initiators had comparable rates of expanded major adverse cardiac events, and HHF or all‐cause death, whereas empagliflozin initiators had a lower rate of a first HHF or loop‐diuretic initiation.
The purpose of this work was to determine the optimal tracer kinetic model of 11C-PIB and to validate the use of the simplified methods retention index (RI) and standardized uptake value (SUV) for ...quantification of cardiac 11C-PIB uptake in amyloidosis.
Single-tissue, reversible and irreversible two-tissue models were fitted to data from seven cardiac amyloidosis patients who underwent 11C-PIB PET scans and arterial blood sampling for measurement of blood radioactivity and metabolites. The irreversible two-tissue model (2Tirr) best described cardiac 11C-PIB uptake. RI and SUV showed high correlation with the rate of irreversible binding (Ki) from the 2Tirr model (r2 =0.95 and r2 =0.94). Retrospective data from 10 amyloidosis patients and 5 healthy controls were analyzed using RI, SUV, as well as compartment modelling with a population-average metabolite correction. All measures were higher in amyloidosis patients than in healthy controls (p=.001), but with an overlap between groups for Ki.
An irreversible two-tissue model best describes the 11C-PIB uptake in cardiac amyloidosis. RI and SUV correlate well with Ki from the 2Tirr model. RI and SUV discriminate better between amyloidosis patients and controls than Ki based on population-average metabolite correction.
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