Lipoprotein(a) [Lp(a)] is a genetically determined, low-density lipoprotein-like particle that has emerged as an important and independent contributor to atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Elevated Lp(a) concentrations, defined as approximately 125 nmol/L (≥ 50 mg/dL) by most consensus thresholds, affect an estimated 20
Zilebesiran is an investigational RNA interference therapeutic that lowers blood pressure by silencing hepatic angiotensinogen, thereby offering sustained antihypertensive activity with infrequent dosing in selected ambulatory populations. This profile is attractive for long-term blood pressure control, but it also raises an unresolved clinical question: how should acute illness be managed when upstream renin–angiotensin system suppression cannot be rapidly attenuated? In this Current Opinion, we place that question in perspective using available trial data, cardiorenal physiology, and acute-care literature. Early-phase studies established that zilebesiran produces sustained angiotensinogen suppression and blood pressure reduction, while also showing that the antihypertensive response is modulated by dietary sodium intake and background renin–angiotensin–aldosterone system blockade. Phase 2 studies then confirmed antihypertensive efficacy in clinically stable outpatient populations, and KARDIA-3 extended evaluation to patients with uncontrolled hypertension and established or high cardiovascular risk receiving multiple antihypertensive agents; however, the study did not meet its prespecified multiplicity-adjusted threshold for statistical significance at month 3. The concern is not that harm has been demonstrated, but that prolonged angiotensinogen silencing may reduce short-term therapeutic flexibility during sepsis, perioperative stress, acute heart failure, marked volume depletion, or hyperkalemia—settings in which clinicians often rely on temporary adjustment of oral renin–angiotensin–aldosterone system inhibitors. Early reversal strategies are conceptually important, but current approaches appear better suited to planned de-escalation than emergency rescue. Future work should define vulnerable phenotypes, clarify whether acute-care pathways require protocol adaptation, and determine how reversibility can be operationalized as phase 3 development advances.
Physical inactivity causes a significant burden from cardiovascular disease worldwide. As sedentary behaviours become increasingly prevalent, there is a growing imperative to explore practical strategies to mitigate cardiovascular risk. This systematic review and meta-analysis aimed to evaluate the association between physical activity in the form of stair climbing and cardiovascular risk. A systematic search of the PubMed and Embase databases was conducted from inception until 8 April 2025. Randomised controlled trials or observational studies including stair climbing as a variable were included. The outcomes of interest were cardiovascular mortality and incidence of cardiovascular disease including myocardial infarction, ischaemic stroke and heart failure. Statistical analyses were conducted using the Review Manager (RevMan) software. The database search yielded 1873 studies, out of which, nine studies with 480,479 patients were included in the analysis. The pooled analysis of five studies and 455,619 patients revealed that stair climbing was associated with a significant reduction in cardiovascular mortality (relative risk [RR] 0.61, 95
While not all angiotensin receptor blockers (ARBs) exhibit inverse agonistic activity, certain ARBs with this property may offer greater potential for blood pressure (BP) reduction compared with ARBs without inverse agonism. This study aimed to evaluate the antihypertensive efficacy and safety of ARBs with or without inverse agonism. A systematic literature review and network meta-analysis identified randomized clinical trials (RCTs) of first-line monotherapy for mild-to-moderate hypertension: azilsartan medoxomil (AZL-M), candesartan, olmesartan, losartan, valsartan, telmisartan, irbesartan, allisartan isoproxil, sacubitril/valsartan, sacubitril/allisartan, or placebo. Treatments were grouped as ARBs with or without inverse agonism, angiotensin receptor neprilysin inhibitors (ARNIs), and placebo. AZL-M was separately analyzed as part of ARBs with inverse agonism. BP changes and adverse events (AEs) were assessed. Of 2659 RCTs screened, 23 studies were analyzed. ARBs with inverse agonism demonstrated superior systolic BP and diastolic BP reductions compared with ARBs without inverse agonism, ARNIs, and placebo. When analyzed separately, AZL-M significantly outperformed ARBs without inverse agonism in systolic BP and diastolic BP reduction and was superior to other ARBs with inverse agonism in systolic BP reduction. Surface under the cumulative ranking curves (SUCRA) indicated AZL-M had the highest probability of being the best treatment for systolic BP (98
Short-term studies have demonstrated that single-pill combinations (SPCs) improve adherence, reduce hypertension-related complications, and lower costs; however, long-term benefits remain unclear. This study compared adherence, healthcare resource utilization (HCRU), and costs over 11 years in patients treated with SPCs versus free-pill combinations (FPCs) of antihypertensive drugs in routine Italian practice. We analyzed a large administrative dataset (2010–2022) covering approximately 7 million Italian citizens. Adults initiating perindopril (PER)-based SPC or FPC with amlodipine and/or indapamide were included. PER-based therapies were selected because their SPCs were among the first marketed in Italy, allowing for extended follow-up. Adherence was measured by proportion of days covered (PDC), with high adherence defined as PDC ≥ 80
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and sacubitril/valsartan (SAC/VAL), an angiotensin receptor-neprilysin inhibitor, are both US Food and Drug Administration-approved and guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF). While each has demonstrated significant reductions in cardiovascular morbidity and mortality, direct comparative evidence remains limited, particularly in relation to patients’ diabetes status. To compare the effectiveness of SAC/VAL versus SGLT2i in preventing HF-related and all-cause hospitalizations among patients with HFrEF, with or without diabetes, using real-world data from the MarketScan® Research databases. This new-user, active-comparator cohort study using MarketScan® Commercial and Medicare databases (2019–2023) identified patients with HFrEF by using International Classification of Diseases codes. Patients who initiated SAC/VAL or SGLT2i treatment were included, with the index date defined as the first prescription fill. Continuous health plan enrollment ≥ 6 months prior to HFrEF diagnosis through the index date was required. To balance baseline characteristics between groups, we applied stabilized inverse probability of treatment weighting (IPTW). Cox proportional hazards models compared risks of HF-related and all-cause hospitalizations in cohort analyses defined by diabetes status, diagnosis, and antidiabetic medications. After IPTW, the study included 7406 patients initiating SAC/VAL and 5101 patients initiating SGLT2i. Among patients with diabetes, there were no significant differences in the risks of HF-related hospitalization (adjusted hazard ratio [aHR] 1.13, 95
Lorundrostat has emerged as a promising therapy for uncontrolled and/or resistant hypertension, with multiple systematic reviews and meta-analyses (SRMAs) evaluating its blood pressure effects and hyperkalemia risk. Despite drawing from identical trials, reported effect sizes varied markedly, warranting an umbrella review. Conducted per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420261358169), this umbrella review included SRMAs of lorundrostat in adults with uncontrolled hypertension. Pooled estimates for systolic blood pressure (SBP), diastolic blood pressure (DBP), and hyperkalemia risk were extracted and compared. Methodological quality was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), and primary study overlap was quantified via corrected covered area (CCA). Ten SRMAs were included; seven focused exclusively on lorundrostat, all showing complete overlap (CCA = 100
Current guidelines recommend single antiplatelet therapy (SAPT) with aspirin for most patients undergoing transcatheter aortic valve implantation (TAVI). However, the optimal choice of SAPT, namely aspirin or clopidogrel, remains uncertain. Our study aims to compare the impact of aspirin versus clopidogrel monotherapy on all-cause mortality in patients after TAVI. Consecutive patients undergoing TAVI treated with single antiplatelet treatment (aspirin or clopidogrel) at two tertiary hospitals between 2012 and 2024 were studied. The primary endpoint was long-term survival over a median follow-up of 49.2 months. Propensity score matching was performed to adjust for baseline differences. Among 982 patients who underwent transcatheter aortic valve implantation and were treated with single antiplatelet therapy, 730 received aspirin, and 252 received clopidogrel. Patients treated with clopidogrel more frequently had a history of ischemic stroke and prior percutaneous coronary intervention and had lower preprocedural peak transvalvular velocity. Overall survival did not differ significantly between patients treated with aspirin and those with clopidogrel (101.0 months [52.7–149.3] versus 88.3 [49.3–127.3], P = 0.390). After propensity score matching, 141 pairs were identified, and long-term survival remained similar between the two groups (108.7 months [54.6–156.8] versus 88.3 [48.5–117.6], P = 0.204). To the best of our knowledge, this is the largest study comparing aspirin versus clopidogrel following TAVI. Our analysis showed comparable long-term survival in patients treated with either aspirin or clopidogrel. Further randomized trials are required for the validation of our results.
Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by pathological pulmonary vascular remodeling leading to right heart failure. Ralinepag extended-release (XR), is a once-daily oral prostacyclin (IP) receptor to treat PAH. This study evaluated the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses of ralinepag XR tablets in fed and fasted healthy adult volunteers. A single-center, open-label, nonrandomized, multiple-dose titration study of two cohorts (fed (n = 13) or fasted (n = 15)) with once-daily dosing of ralinepag XR for 5 days, with up to four sequential dose escalations. Dosing began at 60 µg and escalated every 5 days as tolerated (120, 180, 240, and 300 µg). Doses were administered after a 10-h overnight fast or a moderate-fat breakfast. PK parameters assessed were maximum observed concentration (Cmax), area under the concentration–time curve from time 0 to 24 h postdose (AUC(0–24)), and time of maximum observed concentration (Tmax) on day 1 (single 60 μg dose); and Cmax, AUC(0–24), and Tmax at steady state. Ralinepag XR exhibited minimal differences in PK parameters between fed and fasted states in the first 24 h. Multiple-dose administration showed a dose-dependent increase in exposure and a median 4–10 h Tmax at steady state, independent of fed status. Ralinepag accumulation was approximately 2.1-fold after 5 days of dosing at 60 μg in both fed and fasted states, consistent with a mean half-life of 20–36 h. There were no serious adverse events attributable to ralinepag. The most commonly reported adverse events were headache, jaw pain, and nausea with no differences between groups. Food status did not significantly affect the PK or safety of ralinepag XR.
Artificial intelligence (AI) has emerged as a transformative tool for improving the detection, prediction, and prevention of adverse drug reactions (ADRs) in cardiovascular (CV) medicine, a domain characterized by high drug utilization, complex multimorbidity, and substantial polypharmacy. Traditional pharmacovigilance (PV) systems, particularly spontaneous reporting, remain limited by underreporting, variable data quality, and delayed signal recognition, underscoring the need for computationally enhanced approaches. This narrative review synthesizes current evidence on AI applications across the cardiovascular PV continuum, including safety signal detection, patient-level risk prediction, and text-based surveillance. Machine learning (ML) models, applied to structured datasets such as the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), VigiBase, and electronic health records (EHRs), and curated drug–target databases have shown improved discriminatory performance compared with conventional approaches in identifying bleeding risk under direct oral anticoagulants, predicting acute kidney injury in patients with heart failure, and estimating susceptibility to drug-induced QT prolongation, primarily in internal validation settings. Natural language processing (NLP) advances, particularly transformer-based models, further facilitate extraction of drug–event relationships from clinical notes and patient-generated content. Despite these advances, major challenges persist, including data heterogeneity, selective reporting biases, mechanistic ambiguity in CV ADRs, and limited external validation. Ethical considerations, including privacy preservation, algorithmic transparency, bias mitigation, and human oversight, remain critical for responsible implementation. Looking forward, the integration of real-time biosignal streams from wearable devices, multimodal multiomics data, and explainable AI frameworks may further refine individualized risk assessment and facilitate earlier detection of cardiotoxic events in appropriately validated settings. Collectively, AI holds substantial promise for enhancing cardiovascular drug safety, provided its deployment is accompanied by rigorous validation, robust governance, and alignment with clinical workflows.
Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide cardiovascular benefits in diabetes, but their role in the acute post-myocardial infarction (MI) setting is uncertain. This study evaluated the association of empagliflozin with left ventricular ejection fraction (LVEF) recovery and major adverse cardiac events (MACE) in patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). In a single-center, double-blind, randomized, placebo-controlled trial, patients with STEMI were randomized to empagliflozin 10 mg or placebo daily for 40 days. The primary endpoint was change in left ventricular ejection fraction (LVEF) from baseline to day 40, with sample size calculated a priori based on data from the EMMY trial (minimum 27 per group; 53 per group enrolled). Major adverse cardiac events (MACE)—defined as cardiovascular death, myocardial infarction, or stroke—were assessed as a secondary exploratory endpoint. A total of 117 patients were randomized (59 empagliflozin, 58 placebo), of whom 106 completed follow-up and were analyzed (53 per group). Empagliflozin was associated with significantly greater LVEF recovery at day 40 (mean increase: 7.35
Patients with type 2 diabetes mellitus (T2DM) who survive myocardial infarction (MI) remain at high risk for recurrent cardiovascular events and heart failure (HF). Although glucagon-like peptide-1 receptor agonist (GLP-1 RA) reduces cardiovascular events in stable atherosclerotic disease, its impact among patients with established MI has not been comprehensively synthesized. To evaluate the association between GLP-1 RA use and cardiovascular outcomes in patients with T2DM across MI-defined cohorts. We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Hazard ratios (HRs) with 95
Hypertriglyceridemia can increase the risk of acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD). Patients with familial chylomicronemia syndrome are at an even higher risk of developing pancreatitis due to elevated triglycerides. A pathway involving small interfering RNA that selectively inhibits apolipoprotein C-III (APOC3) messenger RNA through RNA interference is currently being studied to reduce levels of apoC-III and thus, triglycerides. This review presents and discusses the current pharmacokinetic, pharmacodynamics, and clinical and scientific evidence pertaining to plozasiran, a small interfering RNA medicine.
Traditional stroke risk assessment in atrial fibrillation relies on clinical scoring tools such as CHA₂DS₂-VASc, which do not capture the full spectrum of individual thromboembolic risk. Contemporary trials have further challenged this traditional approach, highlighting the importance of atrial fibrillation burden and patient-specific factors in guiding therapy. Advanced echocardiographic markers, including left atrial volume index, strain, and appendage morphology, correlate with atrial remodeling, while biomarkers reflecting cardiac stress and inflammation may further refine risk stratification. These multimodal tools offer a path toward more precise “de-risking” strategies and may help identify patients in whom the net benefit of anticoagulation warrants further individualized assessment. Integrating structural, functional, biomarker, and AI-enabled data into stroke prevention models represents a meaningful step toward personalized care in atrial fibrillation management.
In clinical states of relative aldosterone excess, such as in patients with chronic kidney disease (CKD), blockade of the overactivated mineralocorticoid receptor (MR) is a mechanistically plausible target of therapy in order to improve long-term cardiovascular and kidney outcomes. However, in the recently completed Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK-D) trial, the addition of spironolactone to standard care was not superior to standard care alone in improving cardiovascular outcomes in high-risk patients with moderate CKD. The use of spironolactone over the course of the BARACK-D trial was commonly restricted by hyperkalemia and other side effects. In sharp contrast, finerenone is a novel, selective, non-steroidal MR antagonist with proven cardiorenal protective effects and a more favorable side-effect profile. In a prespecified, individual patient-level data synthesis of 3 large clinical trials, as compared with placebo, finerenone significantly reduced the risks of all-cause death, hospitalization for heart failure and progression of CKD in a broad spectrum of patients with cardio-kidney-metabolic diseases. Although the risk of hyperkalemia with finerenone is real, the permanent discontinuation of treatment due to hyperkalemia occurs rarely. Accordingly, finerenone appears to be a safer therapeutic option with well-documented benefits on cardiovascular and kidney outcomes. In this article, we provide a comparative evaluation of safety and efficacy of spironolactone with that of finerenone. We discuss differences in pharmacodynamic and pharmacokinetic properties as well as data for the safety and efficacy of these 2 MR antagonists. We conclude with a call for a trial aiming to provide a direct and head-to-head comparison between spironolactone and finerenone in high-risk patients with cardio-kidney-metabolic diseases in the future.
Risk assessment models (RAM) use predictive algorithms to support physicians in personalizing care. For example, a RAM to determine the risk of venous thromboembolism (VTE-RAM) in hospitalized patients offered treatment recommendations that physicians adhered to at varying rates. We sought to investigate which factors influenced physician adherence to prophylaxis recommendations from a VTE-RAM implemented in an inpatient setting. We assessed adherence to treatment recommendations for a VTE-RAM in the inpatient setting using both survey and real-world data sources. Inclusion criteria included being a hospitalist or resident in the inpatient setting, using a VTE-RAM at least 50 times, and having complete data from both sources available. Variation in treatment adherence from the two data sources was compared, and physicians were inductively segmented into high- and low-adherence groups. Seven possible factors influencing adherence were identified using prior research and prioritized using best–worst scaling (BWS). Results were stratified by adherence group, and differences in priorities were tested using Wald tests. We obtained data for 188 physicians, most of whom (56
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has emerged as an effective lipid-lowering strategy, particularly for patients with hypercholesterolemia not adequately managed with statins. Ongericimab is a novel monoclonal antibody targeting PCSK9. In this meta-analysis, we aim to evaluate the efficacy and safety of ongericimab in Chinese patients with hypercholesterolemia. A comprehensive literature search was conducted on PubMed, Embase, Scopus, and ClinicalTrials.gov from inception to November 2025, to identify studies assessing the lipid-lowering effects of ongericimab. Effect estimates and 95
