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Aim: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. Methods: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double‐blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta‐analysis was the hazard ratio (HR) for the time to first occurrence of non‐fatal stroke, non‐fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non‐inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non‐fatal stroke, non‐fatal MI or CV death (MACE), tested for non‐inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. Results: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non‐inferiority objective with a P value of less than 0.0001. Non‐inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. Conclusions: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration. [ABSTRACT FROM AUTHOR]

Background: Despite millions of COVID‐19 cases in the United States, it remains unknown whether a history of COVID‐19 infection impacts the safety of pharmacologic myocardial perfusion imaging stress testing (pharmacologic MPI). Hypothesis: The aim of this study was to assess if a prior COVID‐19 infection was associated with a higher risk of complications during and following pharmacologic MPI testing. Methods: This retrospective cohort analysis included 179 803 adults (≥18 years) from the PharMetrics® Plus claims database who underwent pharmacologic MPI between March 1, 2020 and February 28, 2021. Patients with a history of COVID‐19 infection (COVID‐19 group) were compared with propensity‐score matched no‐COVID‐19 history group for reversal agent use, 30‐day resource use, and post‐MPI cardiac events/procedures. Results: The most commonly used stress agent was regadenoson (91.7%). The COVID‐19 group (n = 6372; 3.5%) had slightly higher: reversal agent use (difference 1.13% [95% confidence interval [CI]: 0.33, 1.92]), all‐cause costs (difference USD $128 [95% CI: $73–$181]), and office visits (81.5% vs. 77.0%) than the no‐COVID‐19 group. Prior COVID‐19 infection did not appear to impact subsequent cardiac events/procedures. Conclusions: COVID‐19 history was associated with slightly higher reversal agent use, all‐cause costs, and office visits after pharmacologic MPI; however, the differences were not clinically meaningful. Concerns for use of stress agents in patients with prior COVID‐19 do not appear to be warranted. [ABSTRACT FROM AUTHOR]

Aims: Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes.Methods and Results: In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomerular filtration rate (eGFR); (ii) development of end-stage renal disease; or (iii) death attributable to renal causes. A total of 2306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan versus valsartan was similar between patients with (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.24-0.76) and without (HR 0.63; 95% CI: 0.33-1.18; pinteraction  = 0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (pinteraction  = 0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p < 0.001). A change in the rate of decline of eGFR trajectory was observed 12 months preceding a HF hospitalization, and continued in the post-discharge window to 12 months following hospitalization.Conclusions: Heart failure hospitalization denotes increased risk for kidney disease progression which continues following recovery from HF decompensation in patients with HF with preserved ejection fraction.Clinical Trial Registration: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), ClinicalTrials.gov NCT01920711. [ABSTRACT FROM AUTHOR]

Aim: Relationships of pulmonary artery systolic pressure (PASP) and right ventricular (RV) dysfunction with exercise capacity are understudied. To assess the relationship of PASP and RV function with functional capacity and ventilatory efficiency in heart failure (HF) with a wide range of left ventricular ejection fraction (LVEF). Methods and results: Five hundred thirty‐two consecutive HF patients referred for cardiopulmonary exercise testing [percent predicted peak VO2 (ppVO2), VE/VCO2 slope] and echocardiography [LVEF, PASP, and RV fractional area change (RVFAC)] were studied. Associations of PASP and RVFAC with ppVO2 and VE/VCO2 slope were assessed by multivariable linear regression and restricted cubic splines. Associations with composite of death, heart transplant, and LV assist device (median 3.9 year follow‐up) was assessed using multivariable Cox proportional hazard models. Mean age was 56 ± 14 years and mean LVEF was 35 ± 15%. Mean PASP was 34 ± 12 mmHg, RVFAC was 41 ± 13%, ppVO2 was 60 ± 21%, and VE/VCO2 slope was 35 ± 12. After adjusting for demographics, co‐morbidities, LVEF, mitral regurgitation severity, and left atrial volume index, higher PASP was associated with worse ppVO2 (P = 0.004) and was more robust in patients with LVEF ≥45% vs. <45% (Pinteraction = 0.006). Lower RVFAC was associated with both worse ppVO2 (P = 0.002) and higher VE/VCO2 slope (P = 0.002). Higher PASP and lower RVFAC were both associated with heightened risk of composite endpoint (HR 1.07 per 5 mmHg increase, P = 0.03; HR 1.17 per 5% decrease, P <0.001, respectively). Conclusions: In HF across wide range of LVEF, greater PASP and worse RV function predict worse functional capacity and greater respiratory inefficiency, independent of LV structure and function. [ABSTRACT FROM AUTHOR]

Aims: Chronic hyperglycaemia, assessed by elevated glycated haemoglobin (A1C), is a known risk factor for heart failure (HF) and cardiovascular (CV) death among subjects with diabetes. Whether this risk varies with left ventricular ejection fraction (LVEF) is unknown. This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF.Methods and Results: We assessed the relationships of baseline A1C and LVEF with a composite outcome of either CV death or HF hospitalization in the 4091 patients with type 2 diabetes and a recent acute coronary syndrome enrolled in the ELIXA trial who had available LVEF. We assessed for interaction between A1C and LVEF as continuous variables with respect to this outcome. During a median follow-up of 25.7 months, 343 patients (8.4%) had HF hospitalization or died of CV causes. In a multivariable model, A1C and LVEF were each associated with an increased risk of HF hospitalization or CV death [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.21 per 1% higher A1C, and adjusted HR 1.39, 95% CI 1.27-1.51 per 10% lower in LVEF]. Both A1C and LVEF were independently and incrementally associated with risk without evidence of interaction (P for interaction = 0.31). Patients with A1C ≥ 8% and LVEF <40% were at threefold higher risk than those with A1C < 7% and LVEF ≥50% (adjusted HR 3.18, 95% CI 2.03-4.98, P < 0.001).Conclusion: In a contemporary cohort of patients with type 2 diabetes and acute coronary syndrome, baseline chronic hyperglycaemia was associated with an increased risk of HF hospitalization or CV death independently of LVEF. [ABSTRACT FROM AUTHOR]

Background: We examined the association of sex with clinical characteristics and outcomes in patients following myocardial infarction (MI) in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Methods and Results: A total of 4570 women and 10 133 men with heart failure (HF), left ventricular systolic dysfunction or both were enrolled 0.5-10 days after myocardial infarction (MI) and followed for a median of 24.7 months. Compared with men, women were older, had more comorbidities, and were more likely to present in Killip Class III/IV and experience post-infarction angina or HF. After adjusting for baseline differences, both short-term and longer-term mortality were similar in men and women. However, women were more likely than men to experience the composite outcome of cardiovascular death, MI, HF, stroke, and resuscitation from cardiac arrest [adjusted hazard ratio (HR) 1.15; 95% confidence interval (CI); 1.06-1.24, P=0.001], mainly owing to an increased risk of hospitalization for HF (adjusted HR 1.36; 95% CI 1.22-1.52; P<0.001). In a subset of patients who underwent echocardiographic study (n=603), women had smaller left ventricular volumes indexed by body size than men but similar ejection fractions and similar changes in ventricular volumes from baseline to 1 month and 20 months. Conclusions: In VALIANT, the risk of HF following MI was higher in women than men after adjusting for age and comorbidities, although the risk of other fatal and non-fatal outcomes were similar. The higher long-term risk of HF in women appears to be independent of the extent of left ventricular systolic dysfunction or remodelling compared with men. [ABSTRACT FROM AUTHOR]

Aims Hospitalization for worsening heart failure ( HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint. Methods and results MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio ( HR) 12.4, 95% confidence interval ( CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF. Conclusion Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials. Trial Registration NCT01294449. [ABSTRACT FROM AUTHOR]

Aims We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size. Methods and results The ASPIRE trial enrolled 820 patients 2–8 weeks after MI with ejection fraction ≤45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01–2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E′ 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (−4.9 ± 17.9 vs. −5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08). Conclusions Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients. [ABSTRACT FROM PUBLISHER]

Background: While echocardiography is used most frequently to assess right ventricular (RV) function in clinical practice, echocardiography is limited in its ability to provide an accurate measure of RV ejection fraction (RVEF). Hence, quantitative estimation of RV function has proven difficult in clinical practice. Objective: We sought to determine which commonly used echocardiographic measures of RV function were most accurate in comparison with an MRI-derived estimate of RVEF. Methods: We analyzed RV function in 36 patients who had cardiac MRI studies and echocardiograms within a 24 hour period. 2D parameters of RV function—right ventricular fractional area change (RVFAC), tricuspid annular motion (TAM), and transverse fractional shortening (TFS) were obtained from the four-chamber view. RV volumes and EFs were derived from volumetric reconstruction based on endocardial tracing of the RV chamber from the short axis images. Echocardiographic assessment of RV function was correlated with MRI findings. Results: RVFAC measured by echocardiography correlated best with MRI-derived RVEF (r = 0.80, P < 0.001). Neither TAM (r = 0.17; P = 0.30) nor TFC (r = 0.12; p< 0.38) were significantly correlated with RVEF. Conclusions: RVFAC is the best of commonly utilized echocardiographic 2D measure of RV function and correlated best with MRI-derived RV ejection fraction. Condensed Abstract: While echocardiography is used most frequently to assess RV function in clinical practice, echocardiography is limited in its ability to provide an accurate measure of RV ejection fraction (RVEF). Using cardiac MRI, RV fractional area change (RVFAC), determined either by MRI or echocardiography, was found to correlate best with MRI-derived RVEF. [ABSTRACT FROM AUTHOR]

Background: In randomized controlled trials (RCTs) of subjects with type 2 diabetes mellitus, mortality rates vary substantially. We sought to examine the inclusion and exclusion criteria of these RCTs to explore relationships with mortality., Methods and Results: MEDLINE database was searched from August 1980 through March 2011. Selection criterion included published RCTs of adults with type 2 diabetes mellitus of at least 1000 patients, reporting all-cause mortality and having follow-up duration of at least 1 year. Twenty-two trials were eligible. Annualized mortality rates were derived. Inclusion and exclusion criteria were tabulated for each trial. Trials were categorized in 4 groups according to annual mortality rates: <1, ≥1 to <2, ≥2 to <4, and ≥4 per 100 patient-years. The analysis cohort included 91842 patients and 6837 deaths. Mortality rates ranged from 0.28 to 8.24 per 100 patient-years. Patients enrolled in the highest mortality category were more likely to be older and had longer diabetes duration and higher blood pressure. The selection for hypertension was common in the low- as well as high-mortality trials. Although the mortality rates were higher in RCTs with prior cardiovascular morbidity, the selection for chronic kidney disease-defined by either higher serum creatinine or lower estimated glomerular filtration rate and/or the presence of proteinuria-was associated with the highest mortality rates., Conclusions: In this analysis of RCTs of type 2 diabetes mellitus, a 29-fold difference in annualized mortality was observed. In these RCTs, selection for renal disease, defined by either decline in renal function or presence of proteinuria, portends important mortality risk. (J Am Heart Assoc. 2012;1:8-15.), Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00303979.