Effects of Sotagliflozin on Health Status in Patients With Worsening Heart Failure: Results From SOLOIST-WHF.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. OBJECTIVES: These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. METHODS: SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. RESULTS: Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (Ptrend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). CONCLUSIONS: Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934).

Competing Risks in Clinical Trials: Do They Matter and How Should We Account for Them?

During patient follow-up in a randomized trial, some deaths may occur. Where death (or noncardiovascular death) is not part of an outcome of interest it is termed a competing risk. Conventional analyses (eg, Cox proportional hazards model) handle death similarly to other censored follow-up. Patients still alive are unrealistically assumed to be representative of those who died. The Fine and Gray model has been used to handle competing risks, but is often used inappropriately and can be misleading. We propose an alternative multiple imputation approach that plausibly accounts for the fact that patients who die tend also to be at high risk for the (unobserved) outcome of interest. This provides a logical framework for exploring the impact of a competing risk, recognizing that there is no unique solution. We illustrate these issues in 3 cardiovascular trials and in simulation studies. We conclude with practical recommendations for handling competing risks in future trials.

Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome.

BACKGROUND: It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations. OBJECTIVES: This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial. METHODS: Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations. RESULTS: Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82). CONCLUSIONS: Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

Colchicine for cardiovascular and limb risk reduction in Medicare beneficiaries with peripheral artery disease: emulation of target trials.

Aims: Recent evidence from randomized trials demonstrates that colchicine can reduce the risk of major adverse cardiovascular events (MACE) in patients with coronary artery disease. Colchicine's effect on lower-extremity peripheral artery disease (PAD) is not known. Methods and results: To make inferences about the real-world effectiveness of colchicine in PAD, we emulated two target trials leveraging the variable prescribing practice of adding colchicine vs. a non-steroidal anti-inflammatory drug (NSAID) to urate-lowering therapy in patients with gout and PAD. Emulated Trial 1 compared colchicine initiators with NSAID initiators. Emulated Trial 2 compared long-term (indefinite) and short-term (3 months) treatment strategies after initiating colchicine. Eligible individuals were those continuously enrolled in Medicare receiving care at a multicentre academic health system between July 2007 and December 2019. The primary outcome for both trials was a 2 year composite of major adverse limb events (MALE), MACE, and all-cause mortality. Secondary outcomes included MALE and death, MACE and death, and individual components of the primary outcome. Inverse probability weighting was used to adjust for confounding. Percentile-based 95% confidence intervals (CIs) were estimated using non-parametric bootstrapping. A total of 1820 eligible patients were included; the mean age was 77 years [standard deviation (SD) 7], 32% were female, and 9% were non-White. The mean (SD) duration of colchicine and NSAID therapy was 247 (345) and 137 (237) days, respectively. In the emulation of Trial 1, the risk of the primary composite outcome of MALE, MACE, and death at 2 years was 29.9% (95% CI 27.2%, 32.3%) in the colchicine group and 31.5% (28.3%, 34.6%) in the NSAID group, with a risk difference of -1.7% (95% CI -6.5%, 3.1%) and a risk ratio of 0.95 (95% CI 0.83, 1.07). Similar findings were noted in the emulation of Trial 2, with a risk of the primary composite outcome at 2 years of 30.7% (95% CI 23.7%, 38.1%) in the long-term colchicine group and 33.4% (95% CI 29.4%, 37.7%) in the short-term group, with a risk difference of -2.7% (95% CI -10.3%, 5.4%) and risk ratio of 0.92 (95% CI 0.70, 1.16). Conclusion: In a real-world sample of patients with PAD and gout, estimates of the effect of colchicine were consistent across two analyses and provided no conclusive evidence that colchicine decreased the risk of adverse cardiovascular or limb events and death. The cardiovascular and limb benefits of colchicine in older, comorbid populations with PAD and advanced systematic atherosclerosis remain uncertain.

Multimodal fusion learning for long QT syndrome pathogenic genotypes in a racially diverse population.

Congenital long QT syndrome (LQTS) diagnosis is complicated by limited genetic testing at scale, low prevalence, and normal QT corrected interval in patients with high-risk genotypes. We developed a deep learning approach combining electrocardiogram (ECG) waveform and electronic health record data to assess whether patients had pathogenic variants causing LQTS. We defined patients with high-risk genotypes as having ≥1 pathogenic variant in one of the LQTS-susceptibility genes. We trained the model using data from United Kingdom Biobank (UKBB) and then fine-tuned in a racially/ethnically diverse cohort using Mount Sinai BioMe Biobank. Following group-stratified 5-fold splitting, the fine-tuned model achieved area under the precision-recall curve of 0.29 (95% confidence interval [CI] 0.28-0.29) and area under the receiver operating curve of 0.83 (0.82-0.83) on independent testing data from BioMe. Multimodal fusion learning has promise to identify individuals with pathogenic genetic mutations to enable patient prioritization for further work up.

Trends and Outcomes of Acute Myocardial Infarction During the Early COVID-19 Pandemic in the United States: A National Inpatient Sample Study.

BACKGROUND AND OBJECTIVES: There are limited national data on the trends and outcomes of patients hospitalized with acute myocardial infarction (AMI) during the coronavirus disease 2019 (COVID-19) pandemic. We aimed to evaluate the impact of early COVID-19 pandemic on the trends and outcomes of AMI using the National Inpatient Sample (NIS) database. METHODS: The NIS database was queried from January 2019 to December 2020 to identify adult (age ≥18 years) AMI hospitalizations and were categorized into ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) based on International Classification of Diseases, Tenth Revision, Clinical Modification codes. In addition, the in-hospital mortality, revascularization, and resource utilization of AMI hospitalizations early in the COVID-19 pandemic (2020) were compared to those in the pre-pandemic period (2019) using multivariate logistic and linear regression analysis. RESULTS: Amongst 1,709,480 AMI hospitalizations, 209,450 STEMI and 677,355 NSTEMI occurred in 2019 while 196,230 STEMI and 626,445 NSTEMI hospitalizations occurred in 2020. Compared with those in 2019, the AMI hospitalizations in 2020 had higher odds of in-hospital mortality (adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], [1.23-1.32]; p<0.01) and lower odds of percutaneous coronary intervention (aOR, 0.95 [0.92-0.99]; p=0.02), and coronary artery bypass graft (aOR, 0.90 [0.85-0.97]; p<0.01). CONCLUSIONS: We found a significant decline in AMI hospitalizations and use of revascularization, with higher in-hospital mortality, during the early COVID-19 pandemic period (2020) compared with the pre-pandemic period (2019). Further research into the factors associated with increased mortality could help with preparedness in future pandemics.

Role of anticoagulation therapy in modifying stroke risk associated with new-onset atrial fibrillation after non-cardiac surgery.

The role of antithrombotic therapy in the prevention of ischemic stroke after non-cardiac surgery is unclear. In this study, we tested the hypothesis that the association of new-onset postoperative atrial fibrillation (POAF) on ischemic stroke can be mitigated by postoperative oral anticoagulation therapy. Of 251,837 adult patients (155,111 female (61.6%) and 96,726 male (38.4%)) who underwent non-cardiac surgical procedures at two sites, POAF was detected in 4,538 (1.8%) patients. The occurrence of POAF was associated with increased 1-year ischemic stroke risk (3.6% versus 2.3%; adjusted risk ratio (RRadj) = 1.60 (95% confidence interval (CI): 1.37-1.87), P < 0.001). In patients with POAF, the risk of developing stroke attributable to POAF was 1.81 (95% CI: 1.44-2.28; P < 0.001) without oral anticoagulation, whereas, in patients treated with anticoagulation, no significant association was observed between POAF and stroke (RRadj = 1.04 (95% CI: 0.71-1.51), P = 0.847, P for interaction = 0.013). Furthermore, we derived and validated a computational model for the prediction of POAF after non-cardiac surgery based on demographics, comorbidities and procedural risk. These findings suggest that POAF is predictable and associated with an increased risk of postoperative ischemic stroke in patients who do not receive postoperative anticoagulation.

Clonal hematopoiesis, cardiovascular events and treatment benefit in 63,700 individuals from five TIMI randomized trials.

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), Pint = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.

Risk of Bleeding Among Cangrelor-Treated Patients Administered Upstream P2Y12 Inhibitor Therapy: The CAMEO Registry.

Background: Little is known about the bleeding risk associated with cangrelor use in patients with myocardial infarction (MI) who are exposed to an oral P2Y12 inhibitor before coronary angiography. Methods: Cangrelor in Acute MI: Effectiveness and Outcomes (CAMEO) is an observational registry studying platelet inhibition for patients with MI. Upstream oral P2Y12 inhibition was defined as receipt of an oral P2Y12 inhibitor within 24 hours before hospitalization or in-hospital before angiography. Among cangrelor-treated patients, we compared bleeding after cangrelor use through 7 days postdischarge between patients with and without upstream oral P2Y12 inhibitor exposure. Results: Among 1802 cangrelor-treated patients with MI, 385 (21.4%) received upstream oral P2Y12 inhibitor treatment. Of these, 101 patients (33.8%) started cangrelor within 1 hour, 103 (34.4%) between 1 and 3 hours, and 95 (31.8%), >3 hours after in-hospital oral P2Y12 inhibitor administration; the remaining received an oral P2Y12 inhibitor before hospitalization. There was no statistically significant difference in rates of bleeding among cangrelor-treated patients with and without upstream oral P2Y12 inhibitor exposure (6.5% vs 8.8%; adjusted odds ratio [OR], 0.62; 95% CI, 0.38-1.01). Bleeding was observed in 5.0%, 10.7%, and 3.2% of patients treated with cangrelor <1, 1 to 3, and >3 hours after the last oral PY12 inhibitor dose, respectively; bleeding rates were not statistically different between groups (1-3 hours vs <1 hour: adjusted OR, 2.70; 95% CI, 0.87-8.32; >3 hours vs <1 hour: adjusted OR, 0.65; 95% CI, 0.15-2.85). Conclusions: Bleeding risk was not observed to be significantly higher after cangrelor treatment in patients with and without upstream oral P2Y12 inhibitor exposure.

GLP-1 Receptor Agonists Among Patients With Overweight or Obesity, Diabetes, and HFpEF on SGLT2 Inhibitors.

BACKGROUND: Although the use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) in patients with obesity and heart failure with preserved ejection fraction (HFpEF) has demonstrated improvement in cardiovascular outcomes, the incremental benefits of GLP-1 RA for patients already on sodium-glucose cotransporter 2 inhibitors (SGLT2is) remain underexplored. OBJECTIVES: This study aimed to assess the incremental benefits of GLP-1 RA in patients with type 2 diabetes mellitus, overweight/obesity, and HFpEF receiving SGLT2i therapy. METHODS: The authors conducted a retrospective cohort study using the TriNetX research database including patients ≥18 years with type 2 diabetes mellitus, body mass index ≥27 kg/m2, and HFpEF on SGLT2i. Two cohorts were created based on GLP-1 RA prescription. The outcomes were heart failure exacerbation, all-cause emergency department visits/hospitalizations among others over a 12-month period. RESULTS: A total of 7,044 patients remained in each cohort after propensity score matching. There was a significantly lower risk of heart failure exacerbations, all-cause emergency department visits/hospitalizations, new-onset atrial arrhythmias, new-onset acute kidney injury, and pulmonary hypertension in the GLP-1 RA plus SGLT2i cohort compared with the SGLT2i-only cohort. The associated benefits persisted across different body mass indexes and ejection fractions as well as in patients with elevated natriuretic peptide. The risk of diabetic retinopathy was higher in the combination therapy group than with SGLT2i-only use. CONCLUSIONS: GLP-1 RA, in addition to SGLT2i, was associated with a significantly lower risk of heart failure hospitalizations in this patient population, suggesting a potential incremental benefit. This highlights the need for prospective studies to confirm the clinical benefits.

Myocardial Ischemic Syndromes: A New Nomenclature to Harmonize Evolving International Clinical Practice Guidelines.

Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischemia, various classifications have emerged over time, often with conflicting terminology-eg, "stable coronary artery disease" (CAD), "stable ischemic heart disease," and "chronic coronary syndromes" (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with "acute coronary syndromes" (ACS), the 2023 American guidelines endorsed the alternative term "chronic coronary disease." An unintended consequence of these competing classifications is perpetuation of the restrictive terms "coronary" and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of "acute myocardial ischemic syndromes" and "non-acute myocardial ischemic syndromes," which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischemia, and infarction.

Myocardial ischaemic syndromes: a new nomenclature to harmonize evolving international clinical practice guidelines.

Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischaemia, various classifications have emerged over time, often with conflicting terminology-e.g. 'stable coronary artery disease' (CAD), 'stable ischaemic heart disease', and 'chronic coronary syndromes' (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with 'acute coronary syndromes' (ACS), the 2023 American guidelines endorsed the alternative term 'chronic coronary disease'. An unintended consequence of these competing classifications is perpetuation of the restrictive terms 'coronary' and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischaemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of 'acute myocardial ischaemic syndromes' and 'non-acute myocardial ischaemic syndromes', which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischaemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischaemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischaemia and infarction.

Lipoprotein(a) as a cardiovascular risk factor among patients with and without diabetes Mellitus: the Mass General Brigham Lp(a) Registry.

BACKGROUND: Diabetes mellitus (DM) and Lp(a) are well-established predictors of coronary artery disease (CAD) outcomes. However, their combined association remains poorly understood. OBJECTIVE: To investigate the relationship between elevated Lp(a) and DM with CAD outcomes. METHODS: Retrospective analysis of the MGB Lp(a) Registry involving patients ≥ 18 years who underwent Lp(a) measurements between 2000 and 2019. Exclusion criteria were severe kidney dysfunction, malignant neoplasms, and prior atherosclerotic cardiovascular disease (ASCVD). The primary outcome was a combination of cardiovascular death or myocardial infarction (MI). Elevated Lp(a) was defined as > 90th percentile (≥ 216 nmol/L). RESULTS: Among 6,238 patients who met the eligibility criteria, the median age was 54, 45% were women, and 12% had DM. Patients with DM were older, more frequently male, and had a higher prevalence of additional cardiovascular risk factors. Over a median follow-up of 12.9 years, patients with either DM or elevated Lp(a) experienced higher rates of the primary outcome. Notably, those with elevated Lp(a) had a higher incidence of the primary outcome regardless of their DM status. The annual event rates were as follows: No-DM and Lp(a) < 90th% - 0.6%; No-DM and Lp(a) > 90th% - 1.3%; DM and Lp(a) < 90th% - 1.9%; DM and Lp(a) > 90th% - 4.7% (p < 0.001). After adjusting for confounders, elevated Lp(a) remained independently associated with the primary outcome among both patients with DM (HR = 2.66 [95%CI: 1.55-4.58], p < 0.001) and those without DM (HR = 2.01 [95%CI: 1.48-2.74], p < 0.001). CONCLUSIONS: Elevated Lp(a) constitutes an independent and incremental risk factor for CAD outcomes in patients with and without DM.

Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials.

BACKGROUND: SGLT2 inhibitors and GLP-1 receptor agonists both improve cardiovascular and kidney outcomes in patients with type 2 diabetes. We sought to evaluate whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists. METHODS: We conducted a collaborative meta-analysis of trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium, restricted to participants with diabetes. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis. The two main cardiovascular outcomes assessed included major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and hospitalisation for heart failure or cardiovascular death. The main kidney outcomes assessed were chronic kidney disease progression (≥40% decline in estimated glomerular filtration rate [eGFR], kidney failure [eGFR <15 mL/min/1·73 m2, chronic dialysis, or kidney transplantation], or death due to kidney failure), and the rate of change in eGFR over time. Safety outcomes were also assessed. FINDINGS: Across 12 randomised, double-blind, placebo-controlled trials, 3065 (4·2%) of 73 238 participants with diabetes were using GLP-1 receptor agonists at baseline. SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR] 0·81, 95% CI 0·63-1·03 vs 0·90, 0·86-0·94; p-heterogeneity=0·31). Effects on hospitalisation for heart failure or cardiovascular death (0·76, 0·57-1·01 vs 0·78, 0·74-0·82; p-heterogeneity=0·90) and chronic kidney disease progression (0·65, 0·46-0·94 vs 0·67, 0·62-0·72; p-heterogeneity=0·81) were also consistent regardless of GLP-1 receptor agonist use, as was the effect on the chronic rate of change in eGFR over time (heterogeneity=0·92). Fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk 0·87, 95% CI 0·79-0·96 vs 0·91, 0·89-0·93; p-heterogeneity=0·41). INTERPRETATION: The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of the background use of GLP-1 receptor agonists. These findings suggest independent effects of these evidence-based therapies and support clinical practice guidelines recommending the use of these agents in combination to improve cardiovascular and kidney metabolic outcomes. FUNDING: National Health and Medical Research Council of Australia and the Ramaciotti Foundation.

Impact of gender in patients with device-related thrombosis after left atrial appendage closure - A sub-analysis from the multicenter EUROC-DRT-registry.

BACKGROUND: Device-related thrombosis (DRT) is a common finding after left atrial appendage closure (LAAC) and is associated with worse outcomes. As women are underrepresented in clinical studies, further understanding of sex differences in DRT patients is warranted. METHODS AND RESULTS: This sub-analysis from the EUROC-DRT-registry compromises 176 patients with diagnosis of DRT after LAAC. Women, who accounted for 34.7% (61/176) of patients, were older (78.0 ± 6.7 vs. 74.9 ± 9.1 years, p = .06) with lower rates of comorbidities. While DRT was detected significantly later in women (173 ± 267 vs. 127 ± 192 days, p = .01), anticoagulation therapy was escalated similarly, mainly with initiation of novel oral anticoagulant (NOAC), vitamin K antagonist (VKA) or heparin. DRT resolution was achieved in 67.5% (27/40) of women and in 75.0% (54/72) of men (p = .40). In the remaining cases, an intensification/switch of anticoagulation was conducted in 50.% (9/18) of men and in 41.7% (5/12) of women. Final resolution was achieved in 72.5% (29/40) cases in women, and in 81.9% (59/72) cases in men (p = .24). Women were followed-up for a similar time as men (779 ± 520 vs. 908 ± 687 days, p = .51). Kaplan-Meier analysis revealed no difference in mortality rates in women (Hazard Ratio [HR]: 1.73, 95%-Confidence interval [95%-CI]: .68-4.37, p = .25) and no differences in stroke (HR: .83, 95%-CI: .30-2.32, p = .72) within 2 years after LAAC. CONCLUSION: Evaluation of risk factors and outcome revealed no differences between men and women, with DRT in women being diagnosed significantly later. Women should be monitored closely to assess for DRT formation/resolution. Treatment strategies appear to be equally effective.

Peripheral artery disease, chronic kidney disease, and recurrent admissions for acute decompensated heart failure: The ARIC study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) has not only been associated with recurrent hospitalization for acute decompensated heart failure (ADHF) but is also associated with chronic kidney disease (CKD), a known risk factor for worse heart failure outcomes. The interaction of CKD with PAD in post-discharge ADHF outcomes is not well known. METHODS: Since 2005, hospitalizations for ADHF were sampled from 4 US regions by the Atherosclerosis Risk in Communities (ARIC) study and classified by physician review. We examined the adjusted association of PAD with 1-year ADHF readmissions, in patients with and without CKD (defined by glomerular filtration rate [GFR] ≤60 mL/min/1.73 m2 [stage 3a or worse]). RESULTS: From 2005 to 2018, there were 1049 index hospitalizations for patients with ADHF (mean age 77 years, 66 % white) with creatinine data, who were discharged alive. Of these, 155 (15 %) had PAD and 66 % had CKD. In comparison to those without PAD, patients with PAD had more comorbid conditions and higher 1-year ADHF readmission rates, irrespective of CKD status. After adjustment, PAD was associated with a greater risk of 1-year ADHF readmissions, both for patients with concomitant CKD (HR, 1.70; 95 % CI: 1.29-2.24) and those without CKD (HR, 1.97; 95 % CI: 1.14-3.40); p-interaction = 0.8. CONCLUSION: Among patients hospitalized with ADHF, those with concurrent PAD have more prevalent cardiovascular comorbidities and higher likelihood of 1-year ADHF readmission, irrespective of CKD status. Integrating a more holistic approach in management of patients with concomitant heart failure, PAD and CKD may be an important strategy to improve the prognosis in this vulnerable population.

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 low-density lipoprotein cholesterol (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).