BACKGROUND:Direct oral anticoagulants (DOACs) are recommended over vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). However, limited accessibility in resource-constrained settings makes it important to identify patient subgroups in whom VKAs may achieve comparable net clinical outcomes (NCOs). OBJECTIVES:The purpose of this study was to identify AF patient subgroups and explore potential predictors of differential treatment benefit to inform anticoagulant selection where DOAC access is limited. METHODS:Individual patient data from the COMBINE-AF data set pooling 4 pivotal randomized trials of DOACs vs VKAs in AF were analyzed. Model-based clustering identified patient subgroups. Heterogeneity of treatment effects for the NCO-a composite of all-cause death, disabling or fatal stroke, and intracranial or fatal bleeding- was explored using Cox regression and gradient boosting analyses adapted for time-to-event data. RESULTS:A total of 58,634 patients were included (29,272 warfarin; 29,362 standard dose DOACs). Two subgroups were identified: a high-risk cluster (mean creatinine clearance 55.1 mL/min, age 75.6 years, body mass index [BMI] 26.6 kg/m2) and a low-risk cluster (mean creatinine clearance 101 mL/min, age 64.2 years, BMI 32.3 kg/m2). DOACs significantly reduced NCOs in the high-risk cluster (HR: 0.86; 95% CI: 0.81-0.92; P < 0.001), but not in the low-risk cluster (HR: 0.93; 95% CI: 0.85-1.03; P = 0.154, p-interaction = 0.115). Primary predictors of treatment heterogeneity were renal function, age, and BMI; no statistically significant treatment-by-subgroup interactions were identified. CONCLUSIONS:Renal function, age, and BMI are key determinants of anticoagulant treatment benefit in AF. In regions with limited access to DOACs, these findings suggest that some lower-risk patient profiles may derive similar outcomes with VKAs, although differences were not statistically significant.

Acute coronary syndromes are caused by obstructive coronary thrombosis complicating myocardial ischaemic disease and are dichotomously classified according to their electrocardiographic presentation as ST-segment elevation myocardial infraction or non-ST-segment elevation acute coronary syndrome, either without or with elevated myocardial necrosis markers. Initial diagnosis and risk stratification are reliably guided by symptoms, electrocardiographic changes, and troponin elevation and require exclusion of alternative conditions, such as Type 2 myocardial infarction and myocardial injury due to systemic conditions. Timely coronary angiography is a key component of the initial diagnosis to assess the presence of occlusive coronary artery disease, rather than an myocardial infarction with non-occluded coronary arteries, and the suitability for revascularization. While clinical trials with randomization prior to angiography have shown reduction in recurrent myocardial infarction and urgent revascularization with a neutral effect on mortality from an early invasive approach, increased revascularization rates have been systematically associated with reduced mortality in registries and administrative databases. Complete revascularization in patients with multivessel disease has been shown to reduce mortality compared with culprit-only revascularization. The safety of this approach has been shown even in fragile, elderly, and multimorbid patients. Post-acute treatment should be focused on patient-tailored antithrombotic therapy and disease-modifying secondary prevention approaches. This review describes the complex spectrum of non-ST-segment elevation acute coronary syndrome and the importance of complete clinical and coronary angiographic assessment for optimal patient-centred treatment.

Atrial failure is an emerging clinical syndrome that results from an underlying atrial cardiomyopathy and is characterized by impaired atrial haemodynamic and/or electrical function that is sufficient to cause symptoms, adverse clinical outcomes or both. Similar to ventricular cardiomyopathy, atrial cardiomyopathy refers to a structural, functional and/or electrophysiological tissue abnormality, whereas atrial failure denotes the stage at which it manifests clinically. Atrial failure can be classified as primary, when driven by intrinsic atrial pathology, or secondary, when atrial dysfunction arises from sustained haemodynamic or electrical stress imposed by ventricular, valvular or systemic disease. Increasing evidence indicates that atrial failure might not be merely a bystander, but a key determinant of symptoms and prognosis in cardiovascular conditions. Atrial failure can act as a primary driver of heart failure with preserved ejection fraction, promote atrial arrhythmias through adverse electrical remodelling, and potentially increase thromboembolic risk independently of atrial fibrillation. In this Review, we detail the pathophysiological mechanisms and clinical phenotypes of atrial failure and highlight the role of multimodality imaging in diagnosing and phenotyping atrial cardiomyopathy and clinical atrial failure. Finally, we summarize emerging therapeutic strategies aimed at potentially reversing atrial adverse remodelling and discuss future directions for integrating atrial failure into clinical practice.

The emergence of gene-based therapies for hypertrophic cardiomyopathy (HCM) represents a pivotal inflection point in cardiovascular medicine, but their successful translation will depend on coordinated advances beyond vector design alone. Here, we propose a fieldwide framework for HCM gene therapy development, encompassing core evaluation, safety and immunosuppression management, endpoint definition, long-term surveillance, and considerations of equity and scalability. We argue that harmonization across these domains is essential to ensure that early clinical signals are interpretable, comparable, and translatable into durable patient benefit. This framework provides a roadmap to guide the transition from early feasibility to broad, equitable implementation.

This Viewpoint from the DSMB of the Women’s Health Initiative studies discusses weighing the evidence of benefits and risks of various estrogen products following the FDA’s decision to remove most box warnings from hormone replacement therapy products.

Aims In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk (FOURIER) trial, the PCSK9 inhibitor evolocumab (Evo) significantly reduced the rate of major adverse cardiovascular events and coronary revascularization. The aim was to investigate the effect of initial randomization to Evo on the incidence of complex coronary revascularization during long-term follow-up. Methods and results In FOURIER, patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) >= 70 mg/dL despite optimized statin therapy were randomized to Evo or placebo. At the end of the trial, patients had the option to be treated with Evo in the open-label extension (OLE) at participating sites. All cases of coronary revascularization were centrally reviewed, and complex revascularization was defined as coronary artery bypass graft surgery (CABG) or complex percutaneous coronary intervention (PCI) using the GLOBAL LEADERS definition. Event rates through 8 years were compared between patients randomized in the parent trial to Evo or placebo. Of 27 564 patients in FOURIER, 6635 patients (median achieved LDL-C 30 mg/dL) continued in OLE (total median follow-up 7.2 years). Patients initially randomized to Evo were treated on average 2.2 years earlier than patients starting treatment during OLE. In patients receiving Evo earlier, the rate for complex coronary revascularization through 8 years was reduced by 24% (HR 0.76 [0.67, 0.87], P < 0.001). This effect was consistent for both CABG (HR 0.77 [0.63, 0.94], P = 0.01) and complex PCI (HR 0.78 [0.65, 0.93], P = 0.006) individually. Early vs. delayed Evo therapy resulted in lower total stent length implanted (22 521 mm vs. 28 946 mm, P < 0.001). Conclusion Compared with delayed treatment initiation, early and sustained treatment with Evo significantly reduced the likelihood of complex revascularization during long-term follow-up. Lay summary Lowering circulating LDL-cholesterol reduces its accumulation in the blood vessels of the heart, legs, and other parts of the body, known as atherosclerosis. Evolocumab is a drug that lowers LDL-cholesterol by similar to 60%. In this study, patients with known atherosclerosis were randomly assigned to receive evolocumab earlier or later. Patients who started evolocumab earlier less frequently needed complex invasive procedures to restore the blood flow to the heart. These results show that early, aggressive lowering of LDL-cholesterol results in fewer coronary bypass surgeries and complex stenting procedures. Trial Registration clinicaltrials.gov, unique identifiers NCT01764633, NCT02867813, and NCT03080935.

BACKGROUND:Systemic embolic events (SEEs) are a serious but underrecognized complication of atrial fibrillation. Although non-vitamin K antagonist oral anticoagulants prevent ischemic stroke (IS), their efficacy in SEE and the clinical characteristics of patients who experience SEE remain poorly understood. METHODS:We analyzed individual patient data from 4 pivotal randomized trials enrolling patients between 2005 and 2010 comparing non-vitamin K antagonist oral anticoagulants versus warfarin in atrial fibrillation. We characterized the incidence, clinical features, management, and outcomes of clinically overt SEE and compared results in these patients with patients who had an IS. RESULTS:Among 71 683 patients, 188 experienced SEE (26 with concurrent IS), yielding an annualized event rate of 0.13% per patient-year, compared with 1.25% per patient-year for IS (n=1797). Among 171 patients with SEE as their first event, median age was 75 years (interquartile range, 68-80), 49.7% were female, and mean±SD CHA2DS2-VASc score was 4.7±1.5. Compared with IS, patients with SEE had higher rates of peripheral arterial disease (PAD, 16.5% versus 5.4%; P<0.001), previous myocardial infarction (24% versus 17%; P=0.02), previous vitamin K antagonist exposure (57% versus 46%; P=0.007), worse renal function (median creatinine clearance 58 versus 62 mL/min; P=0.02), and higher incidence of nonparoxysmal atrial fibrillation (86% versus 80%; P=0.047). Interventions (surgical or percutaneous) were performed in 62 patients (31%) with SEE. Standard-dose non-vitamin K antagonist oral anticoagulants reduced the risk of SEE by 29% compared with warfarin over a median follow-up of 25.2 months (interquartile range, 17.5-32.0; hazard ratio, 0.71 [95% CI, 0.51-0.99]; P=0.04). Thirty-day mortality after SEE was similar to IS (18% versus 17%), and SEE was associated with a nearly 3-fold increased risk of long-term mortality compared with patients without SEE or IS (hazard ratio, 2.85 [95% CI, 2.11-3.85]). Independent predictors of SEE included peripheral artery disease, smoking, nonparoxysmal atrial fibrillation, female sex, previous myocardial infarction, previous stroke or transient ischemic attack, vitamin K antagonist experience, and renal dysfunction. CONCLUSIONS:In this large individual patient data meta-analysis, non-vitamin K antagonist oral anticoagulants significantly reduced the risk of SEE compared with warfarin. Although SEEs were approximately one-tenth as frequent as IS, they were associated with comparable mortality and substantial morbidity.

AIMS:Despite improvements in post-acute myocardial infarction (AMI) care, the risk of subsequent cardiovascular (CV) events remains substantial, particularly heart failure (HF) in patients with left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS:The PARADISE-MI trial randomized 5661 patients with AMI complicated by LVSD and/or pulmonary congestion to sacubitril/valsartan (97/103 mg bid) or ramipril (5 mg bid) at a mean of 4 days post-AMI. This post hoc analysis described the timing and distribution of CV events, and compared treatment effects in early (≤ 3 months) and late (> 3 months) post-AMI periods. RESULTS:Post-AMI, CV events peaked early; HF was the most frequent (16.2/100 patient-years (py)), followed by CV death (11.6/100 py) and recurrent MI (10.9/100 py). Later, HF remained predominant (3.2/100 py vs. 2.6/100 py for MI, p=0.008; CV death 2.1/100 py). Early post-AMI, patients with HF or recurrent MI shared similar profiles. Later, HF patients were predominantly older and female, with greater pulmonary congestion and lower eGFR; recurrent MI patients had more frequent history of coronary revascularization. Only sacubitril/valsartan showed a favorable influence late post-AMI (HR 0.76, 95% CI 0.60-1.00, p=0.05) and expanded CV composite outcome (CV death, HF events, recurrent MI, hospitalization for angina, or post-randomization coronary revascularization) benefit over the trial (HR=0.87, 95% CI 0.77-0.97, p=0.012). CONCLUSIONS:Post-AMI, HF predominates both early and late among CV events. Compared with ramipril, sacubitril/valsartan was associated with a possible late reduction in recurrent MI and a modest decrease in an expanded CV composite outcome that merits further investigation.

Since the publication of the landmark EMPA-REG OUTCOME trial, sodium-glucose cotransporter 2 (SGLT2) inhibitors have redefined the therapeutic landscape of cardiovascular-kidney-metabolic disease. Initially developed as glucose-lowering drugs, empagliflozin and subsequent SGLT2 inhibitors have demonstrated robust benefits in reducing hospitalization for heart failure, slowing the progression of chronic kidney disease and lowering cardiovascular mortality across diverse populations. Although the precise mechanisms underlying these effects are not completely understood, the cardioprotective effects of empagliflozin seem to be mediated by an interconnected network of pleiotropic mechanisms. Empagliflozin modulates haemodynamics, restores endothelial and vascular function, improves mitochondrial bioenergetics through increased mitochondrial activity and substrate flexibility, and attenuates maladaptive cardiac remodelling. In this Review, we synthesize the current mechanistic understanding of SGLT2 inhibitors and highlight key directions for the future of cardiovascular-kidney-metabolic disease management. The next decade of research on SGLT2 inhibitors will be shaped by efforts to close evidence gaps, including in kidney failure and cardio-oncology, as well as the integration of SGLT2 inhibitors with other guideline-directed therapies, optimization of therapeutic sequencing and broad implementation in clinical care.

BACKGROUND:In FOURIER, the PCSK9 inhibitor evolocumab (Evo) significantly reduced the rate of major adverse cardiovascular events and coronary revascularization. AIMS:To investigate the effect of evolocumab on the incidence of complex coronary revascularization during long-term follow-up. METHODS:In FOURIER, patients with atherosclerotic cardiovascular disease with LDL-C ≥70mg/dL despite optimized statin therapy were randomized to evolocumab or placebo. At the end of the trial, patients had the option to be treated with evolocumab in the open label extension (OLE) at participating sites. All cases of coronary revascularization were centrally reviewed, and complex revascularization was defined as coronary artery bypass graft surgery (CABG) or complex percutaneous coronary intervention (PCI) using the GLOBAL LEADERS definition. Event rates through 8 years were compared between patients randomized in the parent trial to evolocumab or placebo. RESULTS:Of 27,564 patients in FOURIER, 6,635 patients (median achieved LDL-C 30 mg/dL) continued in OLE (total median follow-up 7.2 years). Patients initially randomized to evolocumab were treated on average 2.2 years earlier than patients starting treatment during OLE. In patients receiving evolocumab earlier, the rate for complex coronary revascularization through 8 years was reduced by 24% (HR 0.76 [0.67, 0.87], p<0.001). This effect was consistent for both CABG (HR 0.77 [0.66, 0.94], p=0.01) and complex PCI (HR 0.78 [0.65, 0.93], p=0.006) individually. Early versus delayed evolocumab therapy resulted in lower total stent length implanted (22,521 mm vs 28,946 mm, p<0.001). CONCLUSION:Compared with delayed treatment initiation, early and sustained treatment with evolocumab significantly reduced the likelihood of complex revascularization during long-term follow-up.

BACKGROUND:Warfarin remains widely used for stroke prevention in atrial fibrillation (AF), particularly where access to direct oral anticoagulants (DOACs) is limited. Updated outcome data across clinical risk groups are needed. OBJECTIVES:The objectives of the study were to identify predictors of adverse outcomes with warfarin, evaluate the TIMI-AF risk score, and assess the benefit of standard-dose (SD) DOACs vs warfarin across risk strata. METHODS:Individual patient-level data from 58,634 patients (29,272 warfarin and 29,362 DOAC) enrolled in 4 pivotal randomized trials were analyzed. The net clinical outcome (NCO), defined as all-cause death, disabling or fatal stroke, or intracranial/fatal bleeding, was assessed using trial-stratified Cox models across key clinical subgroups and TIMI-AF risk score categories. Outcomes with SD-DOACs vs warfarin were compared across risk strata. RESULTS:Older age (adjusted HR [aHR]: 1.55; 95% CI: 1.31-1.83), male sex (aHR: 1.30; 95% CI: 1.20-1.40), impaired kidney function (aHR: 2.21; 95% CI: 1.90-2.56), lower body mass index (aHR: 1.25; 95% CI: 1.15-1.36), vitamin K antagonist-naïve status (aHR: 1.17; 95% CI: 1.08-1.27), and nonparoxysmal AF (aHR: 1.31; 95% CI: 1.19-1.44) were independently associated with increased NCO risk (P < 0.001 for each). Annualized NCO rates were 3.5%, 7.6%, and 12.9% in low-, intermediate-, and high-risk TIMI-AF groups (P trend<0.001). SD-DOACs reduced NCO across all risk strata; however, absolute benefit with DOACs was modest in low-risk patients (0.3%; 95% CI: 0.1% to 0.6%). CONCLUSIONS:Several predictors of poor warfarin outcomes were identified. Although SD-DOACs reduced NCO across the risk spectrum, patients with low TIMI-AF scores derived modest absolute benefit. In settings with limited DOAC access, warfarin may be a reasonable option for lower-risk patients.

Background and Aims Large-scale genome-wide association studies have identified common genetic variants that predict the risk of peripheral artery disease (PAD). This study assessed whether a polygenic risk score (PRS) is associated with PAD and the incidence of major adverse limb events (MALE) independent of clinical risk factors in patients with established cardiometabolic disease. Methods A genetic analysis was performed, pooling individual patient-level data from six TIMI trials. The association of a recently validated PAD PRS with prevalent PAD and the incidence of MALE (acute limb ischaemia, chronic limb-threatening ischaemia, major amputation, or peripheral revascularization) was assessed. Results A total of 68 816 patients were included in this analysis, with a median follow-up of 2.6 years. Of these, 5986 (8.7%) had known PAD at baseline. After adjusting for clinical risk factors, a higher PAD PRS was independently associated with a 15% greater odds of prevalent PAD (adjusted odds ratio per 1-SD: 1.15 [95% confidence interval 1.12-1.18], P < .0001), a magnitude of risk as strong as established clinical risk factors. A total of 577 patients experienced MALE during follow-up. A higher PAD PRS was associated with a 30% increased risk of MALE (adjusted hazard ratio per 1-SD: 1.30 [1.19-1.42], P < .0001). Adding the PAD PRS to clinical risk factors resulted in a statistically significant but modest improvement in discrimination (area under the curve went from 0.651 to 0.662 P < .0001). Conclusions In a broad spectrum of patients with cardiometabolic disease, the PAD PRS is associated with an increased risk of PAD and the incidence of MALE beyond clinical risk factors; however, the improvement in discrimination was statistically significant but clinically modest.

BACKGROUND AND AIMS:Large-scale randomized data comparing clinical outcomes of atrial fibrillation patients of Asian vs non-Asian races are limited. METHODS:Data from A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation, which pooled patient-level data from the four pivotal randomized trials of direct oral anticoagulants (DOACs) vs warfarin in patients with atrial fibrillation, were analysed. Baseline characteristics and clinical outcomes in patients of Asian race (Asians) vs non-Asian race were compared. The relative efficacy and safety of DOACs compared with warfarin in Asians vs non-Asians, assessing for interactions between race and treatment effect, were investigated. Outcomes across the range of body weight and creatinine clearance in Asians were also explored. RESULTS:A total of 10 212 Asian patients and 61 471 non-Asians were identified. Compared with non-Asians, Asians were on average 3.2 years younger and 20 kg lighter, had worse renal function (mean creatinine clearance 64.9 vs 77.3 mL/min), and had higher rates of prior stroke/transient ischaemic attack (37.2% vs 26.6%) (P < .001 for each). In the warfarin arm (median time in therapeutic range 57.7% for Asians vs 66.2% for non-Asians, P < .001), Asians had a higher adjusted risk of stroke/systemic embolic events (SEEs), major bleeding, intracranial haemorrhage, gastrointestinal bleeding, and primary net clinical outcome (stroke/SEE, major bleeding, or death). Compared with warfarin, standard-dose (SD) DOACs significantly reduced the risks in Asians to a greater degree than non-Asians for stroke/SEE (hazard ratio [HR] .65, 95% confidence interval .53-.80 vs HR .86, 95% confidence interval .78-.95), major bleeding (HR .62 [.52-.75] vs HR .91 [.84-.98]), and primary net clinical outcome (HR .76 [.68-.85] vs HR .94 [.90-.98]; Pint < .02 for each). Standard-dose DOACs increased gastrointestinal bleeding only in non-Asians (Asians HR .92 [.69-1.23] vs non-Asians HR 1.41 [1.25-1.58], Pint = .009). In Asians, SD DOACs reduced the risks of clinical events across the wide range of body weight and creatinine clearance. Compared with SD DOACs, lower-dose DOACs significantly increased the risk of stroke/SEE (HR 1.57 [1.15-2.13]) and secondary net clinical outcome (stroke/SEE, intracranial haemorrhage, or death; HR 1.23 [1.03-1.48]) in Asians. CONCLUSIONS:Clinical outcomes with SD DOACs vs warfarin in patients with atrial fibrillation were generally even more favourable in patients of Asian than non-Asian race. Compared with warfarin, SD DOACs did not increase the risk of gastrointestinal bleeding in Asians. Standard-dose DOACs are preferred over warfarin or lower-dose DOACs in patients of Asian race.

This Viewpoint advocates for prompt aortic valve replacement (rather than clinical surveillance) as the default strategy for patients with asymptomatic severe aortic stenosis.

Introduction Significant sex-specific differences exist in heart failure with preserved ejection fraction (HFpEF). In particular, sub-analyses of key trials suggest a preferential benefit of specific HFpEF therapies in women. Hypothesis This work investigated potential differential treatment effects between women and men in the PARAGLIDE-HF (Prospective Comparison of ARNI with ARB given following Stabilization in Decompensated HFpEF) trial. We hypothesized that there would be no significant difference in treatment effect among women versus men in this high-risk population with LVEF>40%. Methods In this pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGLIDE-HF trial. The primary endpoint was time-average proportional change in amino terminal pro-B type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. We also examined secondary outcomes and tolerability among women and men. Results Overall, 224 men (48%) and 242 women (52%) were randomized. Women had significantly higher LVEF, worse renal function, and less comorbid atrial fibrillation and coronary artery disease than men. In the overall study population, time-averaged reduction in NT-proBNP was significantly greater for Sacubitril-Valsartan (Sac/Val) than Valsartan (ratio of change 0.85; 95% CI:0.73-0.999). When examined according to sex, time-averaged reduction in NT-proBNP was numerically greater with Sac/Val than Valsartan in both men (ratio of change 0.84; 95% CI:0.67-1.05) and women (ratio of change 0.86; 95% CI:0.69-1.070), especially those with LVEF≤60% (ratio of change 0.75; 95% CI:0.59-0.96 for men; ratio of change 0.79; 95% CI:0.60-1.05 for women), with no significant differential treatment effect based on sex (P for interaction in overall sample=0.91, Figure 1). Similarly, the secondary hierarchical endpoint favored Sac/Val over Valsartan in both men and women but was not statistically significant (Figure 2). With regards to tolerability, study drug dosage levels were similar between Sac/Val and Valsartan across men and women. Likewise, there were no sex-specific differences in the incidence of adverse events. Conclusions The efficacy, safety and tolerability of Sac/Val versus Valsartan were similar in both men and women in the PARAGLIDE-HF trial.