<div><h4>Non-steroidal anti-inflammatory drugs and risk of pulmonary embolism in patients with inflammatory joint disease - results from the nationwide Norwegian Cardio-rheuma registry.</h4><i>Ikdahl E, Rollefstad S, Kazemi A, Provan SA, Larsen TL, Semb AG</i><br /><b>Aims</b><br />Patients with inflammatory joint diseases (IJD), including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) have increased rates of pulmonary embolism (PE). Non-steroidal anti-inflammatory drugs (NSAIDs) use is associated with PE in the general population. Our aim was to evaluate the association between NSAIDs use and PE in IJD patients.<br /><b>Methods and results</b><br />Using individual-level registry data from the whole Norwegian population, including data from the Norwegian Patient Registry and the Norwegian Prescription Database, we: 1) Evaluated PE risk in IJD compared to non-IJD individuals, 2) Applied the self-controlled case series method to evaluate if PE risks were associated with use of traditional NSAIDs (tNSAIDs) and selective cox-2 inhibitors (coxibs).After a one-year wash-out period, we followed 4 660 475 adults, including 74 001 with IJD (RA: 39 050, PsA: 20 803, axSpA: 18 591) for a median of 9.0 years. Crude PE incidence rates per 1000 patient years were 2.02 in IJD and 1.01 in non-IJD individuals. Age and sex adjusted hazard ratios for PE events were 1.57 for IJD patients compared to non-IJD. Incidence rate ratios (IRR) (95% CI) for PE during tNSAIDs use were 0.78 (0.64 to 0.94, P = 0.010) in IJD and 1.68 (1.61-1.76, P < 0.001) in non-IJD. IRR (95% CI) for PE during coxibs use was 1.75 (1.10-2.79, P = 0.018) in IJD and 2.80 (2.47-3.18, P < 0.001) for non-IJD.<br /><b>Conclusion</b><br />PE rates appeared to be higher in IJD than among non-IJD subjects in our study. tNSAIDs may protect against PE in IJD patients, while coxibs may associated with increased PE risk.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 25 Oct 2023; epub ahead of print</small></div>

<div><h4>Effectiveness and Safety of Nonvitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation at Low Risk of Stroke in Japan: A Retrospective Cohort Study.</h4><i>Uchida M, Jo T, Okada A, Matsui H, Yasunaga H</i><br /><b>Aims</b><br />Contemporary guidelines differ in their recommendations regarding initiating nonvitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) at low risk of stroke. This study aimed to examine the effectiveness and safety of NOACs for low-risk AF in a Japanese cohort.<br /><b>Methods and results</b><br />In this retrospective cohort study based on the JMDC Claims Database extracted between April 2011 and November 2022, we identified 13291 patients with AF at low risk of stroke. We performed inverse probability of treatment weighting Cox regression analyses to compare the embolization and bleeding risks between the nontreatment and NOAC groups. Net clinical benefit was defined as the annual incidence of ischemic stroke events prevented by NOACs after subtracting intracranial hemorrhage (ICH) events attributable to NOACs, multiplied by a weighting factor. The incidences of stroke and ICH in the nontreatment group were 0.47 and 0.15 per 100 person-years, respectively. The NOAC group had higher incidences of ICH (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 0.75-4.00) and stroke (HR: 1.41, 95% CI: 0.84-2.36). The net clinical benefit of NOAC treatment was -0.35% per year (95% CI: -0.99-0.29%).<br /><b>Conclusion</b><br />NOAC treatment may be associated with a slightlyhigh risk of ICH, and it yielded a neutral clinical benefit in the present Japanese population, which provides reassurance concerning the role of ethnicity in NOAC treatment for patients with AF and suggests a need to assess comprehensive weighting of the respective risk factors.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 19 Oct 2023; epub ahead of print</small></div>

<div><h4>Novel therapeutic targets and emerging treatments for atherosclerotic cardiovascular disease.</h4><i>Zheng WC, Chan W, Dart A, Shaw JA</i><br /><AbstractText>Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide. Even with excellent control of LDL-C levels, adverse cardiovascular events remain a significant clinical problem worldwide, including among those without any traditional ASCVD risk factors. It is necessary to identify novel sources of residual risk and to develop targeted strategies that address them. Lipoprotein(a) [Lp(a)] has become increasingly recognised as a new cardiovascular risk determinant. Large-scale clinical trials have also signalled the potential additive cardiovascular benefits of decreasing triglycerides beyond lowering LDL-C levels. Since CANTOS (Anti-inflammatory Therapy with Canakinumab for Atherosclerotic Disease) demonstrated that antibodies against interleukin-1β may decrease recurrent cardiovascular events in secondary prevention, various anti-inflammatory medications used for rheumatic conditions and new monoclonal therapeutics have undergone rigorous evaluation. These data build towards a paradigm shift in secondary ASCVD prevention, underscoring the value of targeting multiple biologic pathways in the management of both lipid levels and systemic inflammation. Evolving knowledge of the immune system, and the gut microbiota may result in opportunities for modifying previously unrecognised sources of residual inflammatory risk. This review provides an overview of novel therapeutic targets for ASCVD and emerging treatments with a focus on mechanisms, efficacy, and safety.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 09 Oct 2023; epub ahead of print</small></div>

<div><h4>A novel, small-volume subcutaneous furosemide formulation delivered by an abdominal patch infusor device in patients with heart failure: results of two phase I studies.</h4><i>Osmanska J, Brooksbank K, Docherty KF, Robertson S, ... Petrie MC, Campbell RT</i><br /><b>Aims</b><br />Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early-discharge, preventing hospitalizations and in palliative care. A high concentration, pH neutral furosemide formulation has been developed for SC administration via a small patch-infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK) and pharmacodynamic (PD) profile of a new SC furosemide formulation with conventional IV furosemide, and describe the first use of a bespoke mini-pump to administer this formulation.<br /><b>Methods and results</b><br />A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over five hours) was investigated. The first study was a PK/PD study of SC furosemide compared to 80 mg IV furosemide administered as a bolus in ambulatory patients with heart failure (HF). The primary outcome was absolute-bioavailability of SC compared to IV furosemide. The second study investigated the same SC furosemide preparation delivered by a patch infusor in patients hospitalized with HF. Primary outcome measures were treatment emergent adverse events, infusion site pain, device performance, and PK measurements.The absolute bioavailability of SC furosemide in comparison to IV furosemide was 112%, resulting in equivalent diuresis and natriuresis. When SC furosemide was administered via the patch pump there were no treatment emergent adverse events and 95% of participants reported no/minor discomfort at the infusion site.<br /><b>Conclusion</b><br />The novel preparation of SC furosemide had similar bioavailability to IV furosemide. Administration via a patch pump was feasible and well tolerated.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 06 Oct 2023; epub ahead of print</small></div>

<div><h4>Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.</h4><i>Grymonprez M, Carnoy L, Capiau A, Boussery K, ... Steurbaut S, Lahousse L</i><br /><b>Aims</b><br />The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.<br /><b>Methods and results</b><br />AF patients were included between 2013-2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)) and all-cause mortality risks (aHR 1.07, 95%CI (1.02-1.11)), but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone (aHR 1.27, 95%CI (1.21-1.34)), diltiazem (aHR 1.28, 95%CI (1.13-1.46)), verapamil (aHR 1.36, 95%CI (1.03-1.80)), ticagrelor (aHR 1.50, 95%CI (1.20-1.87)), and clarithromycin (aHR 1.55, 95%CI (1.14-2.11)); and in edoxaban (aHR 1.24, 95%CI (1.06-1.45)), rivaroxaban (aHR 1.25, 95%CI (1.16-1.34)) and apixaban users (aHR 1.27, 95%CI (1.16-1.39)), but not in dabigatran users (aHR 1.07, 95%CI (0.94-1.23)). Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk (aHR 1.31, 95%CI (1.03-1.68)), but not with bleeding or all-cause mortality.<br /><b>Conclusion</b><br />Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 03 Oct 2023; epub ahead of print</small></div>

<div><h4>Predictive value of the thrombotic risk criteria proposed in the 2023 ESC guidelines for the management of ACS: insights from a large PCI registry.</h4><i>Spirito A, Cao D, Sartori S, Sharma A, ... Dangas G, Mehran R</i><br /><b>Aim</b><br />To assess the value of the thrombotic risk criteria proposed in the 2023 guidelines of the European Society of Cardiology (ESC) for the management of acute coronary syndrome (ACS) to predict the ischemic risk after percutaneous coronary intervention (PCI).<br /><b>Methods and results</b><br />Consecutive patients with acute or chronic coronary syndrome undergoing PCI at a large tertiary-care center from 2014 to 2019 were included. Patients were stratified into low, moderate, or high thrombotic risk based on the ESC criteria. The primary endpoint was major adverse cardiovascular events (MACE) at 1 year, a composite of all-cause death, myocardial infarction (MI) and stroke. Secondary endpoints included major bleeding.Among 11,787 patients, 2641 (22.4%) were at low-risk, 5286 (44.8%) at moderate risk, and 3860 (32.7%) at high-risk. There was an incremental risk of MACE at 1-year in patients at moderate (HR 2.53, 95% CI 1.78-3.58) and high-risk (HR 3.39, 95% CI 2.39-4.80) as compared to those at low-risk, due to higher rates of all-cause death and MI. Major bleeding rates were increased in high-risk patients (HR 1.59, 95% CI 1.25-2.02), but similar between the moderate and low-risk group. The Harrell\'s C-index for MACE was 0.60.<br /><b>Conclusions</b><br />The thrombotic risk criteria of the 2023 ESC guidelines for ACS enable to stratify patients undergoing PCI in categories with an incremental 1-year risk of MACE; however, their overall predictive ability for MACE is modest. Future studies should confirm the value of these criteria to identify patients benefiting from an extended treatment with a second antithrombotic agent.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 23 Sep 2023; epub ahead of print</small></div>

<div><h4>Effects of Renin-Angiotensin system blockers on outcomes from COVID-19: A systematic review and meta-analysis of randomised controlled trials.</h4><i>Lee MMY, Kondo T, Campbell RT, Petrie MC, ... Jhund PS, McMurray JJV</i><br /><b>Background:</b><br/>and aims</b><br />Randomised controlled trials (RCTs) have assessed the effects of renin-angiotensin system (RAS) blockers in adults with COVID-19. This meta-analysis provides estimates of the safety and efficacy of treatment with (versus without) RAS blockers from these trials.<br /><b>Methods</b><br />PubMed, Web of Science, and ClinicalTrials.gov were searched (March 1-April 12, 2023). Event/patient numbers were extracted, comparing ACE inhibitor/ARB treatment, to no treatment, for the outcomes: intensive care unit (ICU) admission, mechanical ventilation, vasopressor use, acute kidney injury (AKI), renal replacement therapy (RRT), acute myocardial infarction, stroke/transient ischaemic attack, heart failure, thromboembolic events, and all-cause death. Fixed-effects meta-analysis estimates were pooled.<br /><b>Results</b><br />Sixteen RCTs including 3492 patients were analysed. Compared with discontinuation of RAS blockers, continuation was not associated with increased risk of ICU (RR 0.96, 0.66-1.41), ventilation (RR 0.77, 0.55-1.09), vasopressors (RR 0.92, 0.58-1.44), AKI (RR 1.01, 0.40-2.56), RRT (RR 1.01, 0.46-2.21), or thromboembolic events (RR 1.07, 0.36-3.19). RAS blocker initiation was not associated with increased risk of ICU (RR 0.71, 0.47-1.08), ventilation (RR 1.12, 0.91-1.38), AKI (RR 1.28, 0.89-1.86), RRT (RR 1.66, 0.89-3.12), or thromboembolic events (RR 1.20, 0.06-23.70), although vasopressor use increased (RR 1.27, 1.02-1.57). The RR for all-cause death in the continuation/discontinuation trials was 1.24 (0.80-1.92), and 1.22 (0.96-1.55) in the initiation trials. In patients with severe/critical COVID-19, RAS blocker initiation increased the risk of all-cause death (RR 1.31, 1.01-1.72).<br /><b>Conclusion</b><br />ACE inhibitors and ARBs may be continued in non-severe COVID-19 infection, where indicated. Conversely, initiation of RAS blockers may be harmful in critically ill patients. PROSPERO registration number: CRD42023408926.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J Cardiovasc Pharmacother: 22 Sep 2023; epub ahead of print</small></div>