Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. METHODS: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. RESULTS: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P=0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P=0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P<0.05). CONCLUSIONS: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674.

Effect of Reconstituted Human Apolipoprotein A-I on Recurrent Ischemic Events in Survivors of Acute MI.

BACKGROUND: The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI. OBJECTIVES: This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of cardiovascular (CV) death and recurrent MI. METHODS: The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6 g CSL112) or placebo. RESULTS: The incidence of the composite of CV death and type 1 MI was 11% to 16% lower in the CSL112 group over the study period (HR: 0.84; 95% CI: 0.7-1.0; P = 0.056 at day 90; HR: 0.86; 95% CI: 0.74-0.99; P = 0.048 at day 180; and HR: 0.89; 95% CI: 0.79-1.01; P = 0.07 at day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112-treated patients throughout the follow-up period (HR: 0.92; 95% CI: 0.80-1.05 at day 90, HR: 0.89; 95% CI: 0.79-0.996 at day 180, HR: 0.91; 95% CI: 0.83-1.01 at day 365). The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis). CONCLUSIONS: Although CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared with placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations.

Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

BACKGROUND: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear. METHODS: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up. RESULTS: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group. CONCLUSIONS: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

Left Ventricular Function, Congestion, and Effect of Empagliflozin on Heart Failure Risk After Myocardial Infarction.

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). OBJECTIVES: This study sought to evaluate the association of left ventricular ejection fraction (LVEF), congestion, or both, with outcomes and the impact of empagliflozin in reducing HF risk post-AMI. METHODS: In the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both, to empagliflozin (10 mg daily) or placebo and were followed up for a median of 17.9 months. RESULTS: Among 6,522 patients, the mean baseline LVEF was 41 ± 9%; 2,648 patients (40.6%) presented with LVEF <45% alone, 1,483 (22.7%) presented with congestion alone, and 2,181 (33.4%) presented with both. Among patients in the placebo arm of the trial, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (HR: 1.49; 95% CI: 1.31-1.69; P < 0.0001), first HF hospitalization (HR: 1.64; 95% CI: 1.37-1.96; P < 0.0001), and total HF hospitalizations (rate ratio [RR]: 1.89; 95% CI: 1.51-2.36; P < 0.0001). The presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR: 1.52, 1.94, and RR: 2.03, respectively). Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or congestion, or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. CONCLUSIONS: In patients with AMI, the severity of left ventricular dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion. (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction [EMPACT-MI]; NCT04509674).

Empagliflozin after Acute Myocardial Infarction.

BACKGROUND: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown. METHODS: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis. RESULTS: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups. CONCLUSIONS: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.).

Thrombin as target for prevention of recurrent events after acute coronary syndromes.

The mechanism underlying thrombus formation in acute coronary syndrome (ACS) involves both platelets and thrombin. While both pathways are targeted in acute care, platelet inhibition has been predominantly administered in the chronic phase, yet thrombin plays a key role in platelet activation and fibrin formation. Among ACS patients, there is also a persistent chronic increase in thrombin generation, which is associated with a higher rate of adverse events. In the setting of post-ACS care with rivaroxaban or vorapaxar, targeting thrombin has been associated with decreased thrombin generation and reduced cardiovascular events, but has been associated with increased bleeding risk. We explored the evidence supporting thrombin generation in the pathophysiology of recurrent events post-ACS and the role of thrombin as a viable therapeutic target. One specific target is factor XI inhibition, which is involved in thrombin generation, but may also allow for the preservation of normal hemostasis.

World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Patient Adherence to Secondary Prevention Therapies After an Acute Coronary Syndrome: A Scoping Review.

PURPOSE: Adherence to guideline-recommended, long-term secondary preventative therapies among patients with acute coronary syndrome (ACS) is fundamental to improving long-term outcomes. The purpose of this scoping review was to provide a broad synopsis of pertinent studies in a structured and comprehensive way regarding factors that influence patient adherence to medical therapy after ACS. METHODS: Relevant articles focusing on adherence to medical therapy after ACS were retrieved from the EMBASE and MEDLINE databases (search date, September 7, 2021). Studies were independently screened, and relevant information was extracted. FINDINGS: A total of 58 studies were identified by using the EMBASE and MEDLINE databases. Adherence to secondary prevention was moderate to low and steadily decreased over time. Nearly 30% of patients discontinued one or more medications within 90 days of their primary ACS, and adherence decreased to 50% to 60% at 1 year postdischarge. There were no major differences in adherence between drug classes. Factors influencing patient adherence can be broadly divided into 3 categories: patient related, health care system related, and disease related. Patients managed with percutaneous coronary interventions were more adherent to follow-up treatment than medically managed patients. Depression was reported as a major psychological factor that negatively affected adherence. Improved adherence was observed when higher levels of patient education and provider engagement were delivered during postdischarge follow-up, particularly when scheduled early. Notably, the incidence of major adverse cardiovascular events was lower in hospitals with high 90-day medication adherence than those with moderate or low adherence. IMPLICATIONS: Patient nonadherence to guideline-recommended long-term pharmacologic secondary preventative therapies after ACS is multifactorial. A comprehensive multifaceted approach should be implemented to improve adherence and clinical outcomes. This approach should include key interventions such as early follow-up visits, high medication adherence at 90 days, patient engagement and education, and development of novel interventions that support the 3 broad categories influencing patient adherence as discussed in this review.

Heart rate and death and hospitalization for heart failure in patients with persistent or permanent atrial fibrillation: Insights from the ARISTOTLE trial.

Rate control is fundamental in the treatment of patients with atrial fibrillation (AF). The independent association of heart rate with outcomes and range of heart rate associated with best outcomes remains uncertain. We assessed the relationship between heart rate and clinical outcomes in patients with persistent or permanent AF enrolled in the randomized, double-blind ARISTOTLE trial. In patients with persistent or permanent AF, a faster heart rate is associated with a modest, but statistically significant increase in death and heart failure hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00412984).

Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: The VICTORIA echocardiographic substudy.

AIM: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. METHODS AND RESULTS: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co-primary endpoints were changes in LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high-quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2 ; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI -3.8 ± 15.4 vs. -7.1 ± 20.5 ml/m2 ; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient-years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). CONCLUSIONS: In this pre-specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high-risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). Design, Setting, and Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. Main Outcomes and Measures: Major or clinically relevant nonmajor (CRNM) bleeding. Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). Conclusions and Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.

Heterogeneity of diabetes as a risk factor for major adverse cardiovascular events in anticoagulated patients with atrial fibrillation: an analysis of the ARISTOTLE trial.

AIMS: Whether diabetes without insulin therapy is an independent cardiovascular (CV) risk factor in atrial fibrillation (AF) has recently been questioned. We investigated the prognostic relevance of diabetes with or without insulin treatment in patients in the ARISTOTLE trial. METHODS AND RESULTS: Patients with AF and increased stroke risk randomized to apixaban vs. warfarin were classified according to diabetes status: no diabetes; diabetes on no diabetes medications; diabetes on non-insulin antidiabetic drugs only; or insulin-treated. The associations between such patient subgroups and stroke/systemic embolism (SE), myocardial infarction (MI), and CV death were examined by Cox proportional hazard regression, both unadjusted and adjusted for other prognostic variables. Patients with diabetes were younger and had a higher body mass index. Median CHA2DS2VASc score was 4.0 in patients with diabetes and 3.0 in patients without diabetes. We found no significant difference in stroke/SE incidence across patient subgroups. Compared with no diabetes, only insulin-treated diabetes was significantly associated with higher risk. When adjusted for clinical variables, compared with no diabetes, the hazard ratios (HRs) for MI (95% confidence intervals) were for diabetes on no medication: 1.15 (0.62-2.14); for diabetes on non-insulin antidiabetic drugs: 1.32 (0.90-1.94); for insulin-treated diabetes: 2.34 (1.43-3.82); interaction P = 0.008. HRs for CV death were for diabetes on no medication: 1.19 (0.86-166); for diabetes on non-insulin antidiabetic drugs: 1.12 (0.88-1.42); for insulin-treated diabetes 1.85 (1.36-2.53), interaction P = 0.001. CONCLUSION: In anticoagulated patients with AF, a higher risk of MI and CV death is largely confined to diabetes treated with insulin.

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

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

Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas.

OBJECTIVES: Growth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions. METHODS: Data were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region. RESULTS: GDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AF-death score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions. CONCLUSIONS: In patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry NCT00412984 and NCT00262600.

Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.

BACKGROUND: In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y12 inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function. METHODS: In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial. RESULTS: Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min-1·1.73 m-2, respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL·min-1·1.73 m-2 for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL·min-1·1.73 m-2: 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively. CONCLUSIONS: The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

Post-Stroke Cardiovascular Complications and Neurogenic Cardiac Injury: JACC State-of-the-Art Review.

Over 1.5 million deaths worldwide are caused by neurocardiogenic syndromes. Furthermore, the consequences of deleterious brain-heart interactions are not limited to fatal complications. Cardiac arrhythmias, heart failure, and nonfatal coronary syndromes are also common. The brain-heart axis is implicated in post-stroke cardiovascular complications known as the stroke-heart syndrome, sudden cardiac death, and Takotsubo syndrome, among other neurocardiogenic syndromes. Multiple pathophysiological mechanisms with the potential to be targeted with novel therapies have been identified in the last decade. In the present state-of-the-art review, we describe recent advances in the understanding of anatomical and functional aspects of the brain-heart axis, cardiovascular complications after stroke, and a comprehensive pathophysiological model of stroke-induced cardiac injury.

Call to Action: SARS-CoV-2 and CerebrovAscular DisordErs (CASCADE).

BACKGROUND AND PURPOSE: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic. METHODS: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center. CONCLUSION: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities.

Regional variation in clinical characteristics and outcomes in patients with atrial fibrillation: Findings from the ARISTOTLE trial.

BACKGROUND: Variation in patient characteristics and practice patterns may influence outcomes at a regional level. METHODS: We assessed differences in demographics, practice patterns, outcomes, and the effect of apixaban compared with warfarin in ARISTOTLE (n = 18,201) by prespecified regions: North America, Latin America, Europe, and Asia Pacific. The primary outcomes were stroke/systemic embolism and major bleeding. RESULTS: Compared with other regions, patients from Asia Pacific were younger, more women were enrolled in Latin America. Coronary artery disease was more prevalent in Europe and Asia Pacific had the highest rate of prior stroke and renal impairment. Over 50% of patients in North America were taking ≥9 drugs at randomization, compared with 10% in Latin America. North America had the highest rates of temporary study drug discontinuation and procedures. Time in therapeutic range (INR 2.0-3.0) on warfarin was highest in North America and lowest in Asia Pacific. After adjustment and compared with Europe, patients in Asia Pacific had 2-fold higher risk of stroke/systemic embolism and 3-fold higher risk of intracranial hemorrhage. Patients in Latin America had 2-fold increased risk of all-cause death compared with Europe. The benefits of apixaban compared with warfarin were consistent across regions; there was a pronounced reduction in major bleeding in patients from Asia Pacific compared with other regions (p-interaction = 0.03). CONCLUSIONS: Patients with AF enrolled in prespecified regions in ARISTOTLE had differences in clinical baseline characteristics and practice patterns. After adjustment, patients in Asia Pacific and Latin America had worse outcomes than patients from other regions. The relative benefits of apixaban compared with warfarin were consistent across regions with an even greater treatment effect in the reduction of bleeding in patients from Asia Pacific.