Regulatory science (RS) is a field dedicated to developing and applying scientific methods, tools, standards, and evidence-based frameworks to improve regulatory policies and decision-making related to medical and device products. The acceleration of cardiovascular innovations over the past two decades has underscored the need for efficient evidence generation and streamlined regulatory pathways for new drugs and devices.RS seeks to address these challenges by strengthening the evidence base that informs policy and guidance, enhancing transparency, expediting approval processes, and enabling more agile responses to emerging public health needs. By evaluating innovative trial designs and employing advanced statistical methods, RS can reduce resource demands of clinical trials while preserving scientific integrity. RS also facilitates the standardization of biomarker evaluations and surrogate endpoints, supporting advancements in precision medicine. In addition to clinical evaluation, RS can enhance post-marketing surveillance by utilizing real-world evidence and advanced analytics to promptly identify safety signals, ensuring patient safety and continuous product monitoring. RS also supports global regulatory harmonization efforts, reducing redundancies and accelerating access to therapies across regions.RS aims to guide the development of regulatory policies, refine communication strategies to optimize the use of medical products, and maintain efficient, transparent, and scientifically rigorous regulatory frameworks. Continued investment in RS is essential for improving patient outcomes in cardiovascular medicine by safeguarding safety while accelerating innovation and access to therapies.

Background Chronic limb-threatening ischemia (CLTI) caused by infrapopliteal disease is a major therapeutic challenge, with percutaneous transluminal angioplasty (PTA) associated with high rates of restenosis and reintervention. The LIFE-BTK trial previously demonstrated superior efficacy of the Esprit (Abbott Vascular) BTK drug-eluting resorbable scaffold (DRS) over PTA at 1 year, with sustained benefits at 2 years, with comparable safety at both time points. This report presents the 3-year outcomes. Objectives We aimed to compare the 3-year safety and efficacy of DRS vs PTA in patients with CLTI and infrapopliteal artery disease. Methods In this randomized trial, 261 patients with CLTI were assigned 2:1 to DRS or PTA. The primary efficacy endpoint was freedom from above-ankle amputation in the target limb, target vessel occlusion, clinically driven target lesion revascularization (CD-TLR), and binary restenosis of the target lesion. The primary safety endpoint was freedom from major adverse limb events and perioperative death. Results A total of 57% of patients completed the 3-year follow-up. By Kaplan-Meier analysis, the 3-year primary efficacy endpoint was higher with DRS than PTA (59.5% vs 44.8%; P = 0.0025), binary restenosis occurred less frequently with DRS (38.0% vs 49.0%), and CD-TLR was numerically lower with DRS (10.2% vs 18.4%). Limb salvage remained high and comparable (93.8% vs 95.7%), as did the primary safety endpoint (90.8% vs 94.2%). In multivariable Cox regression at 3 years, treatment with DRS was associated with a lower hazard of CD-TLR compared with PTA (HR: 0.46 [95% CI: 0.22-0.97]), with previous minor amputation, greater preintervention stenosis, higher residual stenosis after predilatation, and use of postprocedure dual antiplatelet therapy being independent predictors of CD-TLR. Subgroup analyses showed that outcomes generally favored DRS for patency and reintervention across most patient and lesion characteristics. Conclusions At 3 years, DRS demonstrated sustained advantages over PTA in preserving vessel patency, with lower restenosis and fewer reinterventions while maintaining a comparable safety profile. These findings support the use of DRS in selected patients with CLTI and infrapopliteal disease. (Pivotal Investigation of Safety and Efficacy of Drug-Eluting Resorbable Scaffold Treatment-Below the Knee [LIFE-BTK]; NCT04227899)

BACKGROUND:GARDENIA is a global, multicentre, prospective, non-interventional study in high-risk atrial fibrillation (AF) patients, who were untreated with anticoagulants. OBJECTIVES:Provide contemporary evidence on reasons for non-treatment with an anticoagulant, and outcomes in high-risk AF patients. METHODS:GARDENIA enrolled 704 AF patients with a CHA2DS2-VA score ≥2 and an elevated risk of bleeding (older age (≥70 years), reduced renal function, concomitant antiplatelet or NSAID use, or other conditions associated with increased bleeding risk), and had not been recently treated with an oral anticoagulant (OAC). Patients were followed for at least 4 months. The two-year risks of mortality, stroke and major bleeding with or without direct OACs (DOACs) in these patients was estimated using the GARFIELD risk score. RESULTS:History of major bleeding (18.7%), physician-assessed high-risk of bleeding (17.1%), and patient refusal (17.6%) were the top reasons for not initiating OACs. The 100-person-year event rates (95% CI) for mortality, stroke/systemic embolism (SE)/transient ischemic attack (TIA), and ISTH major bleeding were 13.22 (10.33, 16.92), 2.12 (1.14, 3.94), and 2.21 (1.13, 3.91), respectively. GARFIELD risk analysis indicated a 31% and 40% increase in the risk of mortality and stroke, respectively, and a ~ 30% decrease in risk of major bleeding, compared to the estimated risk, had the patients been anticoagulated. The study was prematurely terminated due to low rate of patient accrual. CONCLUSIONS:Perceived risk of bleeding was the leading cause for non-treatment with OACs in high-risk AF patients. Risk prediction modelling indicated that the benefits of anticoagulation in stroke and mortality reduction outweigh the risk of bleeding.

A comprehensive treatment strategy including renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and finerenone is recommended to reduce the risk of adverse kidney outcomes in people with chronic kidney disease (CKD) and type 2 diabetes. These therapies, along with glucagon-like peptide-1 receptor agonists, slow the progression of CKD, reflected in long-term decline in estimated glomerular filtration rate (eGFR); however, they may also reduce eGFR within the first 3 months of treatment initiation. The initial eGFR decline observed with renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 inhibitors, and finerenone is linked to beneficial hemodynamic changes that lead to reduction in maladaptive glomerular hypertension and hyperfiltration. These beneficial hemodynamic changes ultimately protect against loss of nephron function and mitigate the risk of end-stage kidney disease. This review presents evidence from randomized controlled trials with these therapies demonstrating that this initial decline in eGFR is usually reversible and generally does not reflect an adverse effect on the kidney. An acute eGFR decline less than 30% does not usually reduce the efficacy of these therapies in people with CKD, type 2 diabetes, or heart failure. The clinical implications of this eGFR decline are discussed, including recommendations for initiating therapies and monitoring kidney function. When considering use of these therapies, an initial eGFR decline less than 30% without significant hyperkalemia or acute adverse kidney events should, in general, not be a barrier to continuation of treatment as it may predict a greater long-term benefit on CKD progression.

Peripheral artery disease (PAD) is a prevalent manifestation of systemic atherosclerosis, associated with elevated risks of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Despite its clinical significance, PAD remains underdiagnosed and undertreated, reflecting substantial gaps in guideline implementation. This review highlights advances in the medical management of PAD, focusing on strategies targeting the metabolic, lipid, immuno-inflammatory, and thrombotic drivers of disease to improve cardiovascular and limb outcomes. Optimal management requires intensive, multifaceted approaches that integrate lifestyle modification (including smoking cessation, a healthy diet, and physical activity), risk factor control, and pharmacologic interventions. Dual pathway antithrombotic therapy with low-dose rivaroxaban and aspirin has emerged as a superior strategy to mitigate both cardiovascular and limb events in patients with high ischaemic risk and non-high bleeding risk. Statins are the first-line lipid-lowering therapy for all patients with PAD, and if low-density lipoprotein cholesterol (LDL-C) goals are not achieved with maximally tolerated doses, adjunctive agents-such as ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i)-should be added. Novel antidiabetic agents, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), confer cardiovascular and renal benefits independent of glycaemic control, with emerging data suggesting that GLP-1 RAs may also reduce limb events. To date, semaglutide remains the only anti-obesity pharmacotherapy that has been demonstrated to reduce cardiovascular events in high-risk patients with overweight or obesity in the absence of diabetes. We propose a phenotype-driven approach to enable refined risk stratification across the PAD spectrum, supporting individualized and, when needed, more intensive management.

Objective We evaluated the effect of cognitive behavioral therapy delivered via a novel digital therapeutic application (app), on antihyperglycemic medication use in adults with type 2 diabetes. Methods Trial participants were randomized to receive access to BT-001 or a control app for 180 days. Antihyperglycemic medications were adjusted as needed consistent with standard of care, and all concomitant therapies were permitted. Change in antihyperglycemic medication from baseline to study exit was compared between treatment groups. Results Among 668 randomized participants, the mean number of antihyperglycemic medications at baseline was 2+1 for both groups. The increase in number or dose of medications from baseline to study exit was greater in the control group compared with the BT-001 group (p for trend=0.0001). Use of glucagon-like peptide-1 receptor agonists was more frequent in the control group throughout the study. Participants in the control group more frequently initiated or increased their dose of insulin (control 3.8%, BT-001 1.5%) and less frequently discontinued or decreased their insulin dose (control 0.9%, BT-001 2.2%) during the treatment period (p=0.006). Conclusions BT-001, the first prescription digital therapeutic authorized for treatment of type 2 diabetes, significantly reduced intensification of antihyperglycemic therapy compared to the control app and reduced insulin usage.

Despite substantial advances in the secondary prevention of cardiovascular disease, atherosclerosis of the coronary arteries and its consequences remain the leading cause of death worldwide. Residual cardiovascular risk refers to the ongoing risk of recurrent cardiovascular events that persists in patients with coronary artery disease despite receiving optimal secondary prevention treatment and effective control of conventional risk factors. Lifestyle modification and therapies modulating thrombosis, blood pressure and LDL-cholesterol levels represent the standard approach for the prevention of recurrent cardiovascular events in patients with coronary artery disease. However, current evidence-based therapies and lifestyle modification strategies only partially modulate the pathophysiological pathways involved in the progression and destabilization of atherosclerotic disease, and other mechanisms might have an important role, accounting, at least in part, for the residual cardiovascular risk in these patients. In this Review, we appraise the available evidence and latest insights into the mechanisms and associated biomarkers of recurrent adverse cardiovascular events and provide perspectives on strategies to reduce residual cardiovascular risk in patients with coronary artery disease. In this Review, Galli and colleagues discuss the mechanisms and associated biomarkers of traditional and emerging factors responsible for the residual risk of recurrent adverse cardiovascular events in patients with coronary artery disease, with a focus on new pathophysiological insights and the therapeutic implications.

Chronic Chagas cardiomyopathy (CCC) is one of the leading causes of heart failure with reduced ejection fraction (HFrEF) in Latin America, yet robust evidence for optimal medical therapy remains scarce. This mini-review examines the results, strengths and limitations of the ANSWER-HF study, a single-center, double-blind randomized clinical trial comparing sacubitril–valsartan with enalapril in 190 patients with CCC-HFrEF over six months. The primary endpoint was change in left ventricular ejection fraction (LVEF). Secondary endpoints included N-terminal pro-B-type natriuretic peptides, echocardiography and functional parameters, clinical events and safety assessments. No significant differences were observed in LVEF, cardiac remodeling, 6-minute walk distance or clinical outcomes between study groups. However, patients randomized to sacubitril–valsartan achieved a significantly greater reduction in NT-proBNP at 6 months. These findings highlight the biological effect of sacubitril-valsartan in this population but reinforces the need for larger, long-term studies, powered to hard clinical endpoints, to further establish the role of sacubitril-valsartan in CCC.

BACKGROUND:Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs). Recently, bempedoic acid was shown to reduce MACEs in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE in patients with PAD is unknown. METHODS:CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL-Inhibiting Regimen) randomized 13 970 patients to bempedoic acid 180 mg or placebo from December 22, 2016, to August 14, 2019. The trial primary end point was MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated MALEs, including adverse events indicating worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Outcomes were assessed as time to first event and total (including recurrent) events with a negative binomial approach. RESULTS:A total of 1624 of the enrolled patients (mean±SD age, 63.9±9.9 years; 915 [56.3%] female) had PAD at baseline. In patients with PAD in the placebo group, 69 (8.3%) had MALEs over a median of 40.6 months, with rate of recurrent events of 4.0%/y. Bempedoic acid reduced the risk of MALEs by 36% (hazard ratio, 0.64 [95% CI, 0.44-0.93]; P=0.018) Bempedoic acid reduced total MALEs by 45% (relative risk, 0.55 [95% CI, 0.35-0.85]; P=0.007). First MACE-4 or MALE was reduced overall by 13% (hazard ratio, 0.87 [95% CI, 0.80-0.95]) with consistent effects with PAD (hazard ratio, 0.82 [95% CI, 0.64-1.04]) and without PAD (hazard ratio, 0.87 [95% CI, 0.79-0.86]; Pinteraction=NS) but not statistically significant within the PAD subgroup alone. Total MACE-4 or MALE was reduced (relative risk, 0.81 [95% CI, 0.73-0.90]) overall with consistent effects in PAD (relative risk, 0.71 [95% CI, 0.54-0.95]) and without PAD (relative risk, 0.82 [95% CI, 0.73-0.92]; Pinteraction=NS). CONCLUSIONS:Patients with PAD are at high risk of MALEs and MACEs. Bempedoic acid reduces both MACEs and MALEs in patients with atherosclerotic vascular disease, with notable absolute benefits in patients with PAD. These findings support (1) the importance of lowering low-density lipoprotein cholesterol in patients with PAD to reduce overall vascular risk and (2) the benefits of bempedoic acid in this population.

BACKGROUND:Individuals with lower extremity peripheral artery disease (LE PAD) represent a subset of patients with atherosclerotic cardiovascular disease that are among the highest risk for major adverse cardiovascular and limb events. Despite this, LE PAD is frequently under diagnosed, and an individual patient's risk for cardiovascular morbidity and limb loss is often underestimated and undertreated. OBJECTIVE:This narrative review aims to explore mechanisms and evidence for secondary prevention therapies to change the course of PAD disease progression. SUMMARY:The cornerstone of secondary prevention is centered on symptom control, lifestyle and behavioural interventions that include exercise therapy, smoking cessation, healthy nutrition and weight management. Individuals with high-risk concomitant comorbidities, such as ongoing smoking, diabetes, and chronic kidney disease, represent an even higher risk population that warrant stringent monitoring and may benefit the most from pharmacological therapies. Guideline-recommended pharmacological therapies include antiplatelet and anticoagulant medications, lipid lowering therapies, diabetes medications, and cilostazol. Despite guideline recommendations, these medical therapies remain under-utilized in patients with PAD. CONCLUSION:Based on the elevated risk profile of individuals with LE PAD undergoing lower extremity revascularization, increased efforts are required to initiate and escalate secondary prevention therapies. To achieve this, the development of effective, patient-centered and scalable implementation strategies remains a priority.

BACKGROUND AND AIMS:In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. METHODS:VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. RESULTS:Over a median of 19.7 months (inter-quartile range 14.6-25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71-0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74-0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56-0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54-0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. CONCLUSIONS:In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

BACKGROUND:Cardiovascular disease remains the leading cause of morbidity and mortality in the United States. JACC Cardiovascular Statistics 2026 reports the most up-to-date data on cardiovascular health in the United States. The report covers major cardiovascular risk factors (hypertension, diabetes, obesity, cholesterol, and cigarette smoking) and conditions that collectively account for most cardiovascular deaths and disability: coronary heart disease, acute myocardial infarction, heart failure, peripheral artery disease, and stroke. OBJECTIVES:JACC Cardiovascular Statistics was developed to provide a clear, comprehensive, and accessible snapshot of cardiovascular health in the United States. An annual synthesis of contemporary cardiovascular statistics is needed to inform patients, clinicians, researchers, public health professionals, policymakers, and the public. METHODS:This report synthesizes data from multiple national sources, including population-based surveys, clinical registries, administrative datasets, and vital statistics. For each risk factor and condition, we evaluated trends in disease epidemiology, quality of care, and morbidity and mortality. Data are presented overall and, where available, stratified by age, sex, race and ethnicity, socioeconomic status, and geography. Findings are presented using a standardized, visually accessible framework. RESULTS:Cardiovascular risk factors-hypertension, diabetes, obesity, cholesterol, and cigarette smoking-remain prevalent among U.S. adults, with persistent gaps in prevention and treatment. Across cardiovascular conditions-coronary heart disease, acute myocardial infarction, heart failure, peripheral artery disease, and stroke-long-term gains in mortality are slowing or reversing, with ongoing gaps in quality of care and persistent health disparities. CONCLUSIONS:JACC Cardiovascular Statistics 2026 provides a comprehensive snapshot of cardiovascular health in the United States, serving as an annual benchmark to guide clinical practice, inform health policy, and promote accountability in efforts to improve cardiovascular health and outcomes for all.