<div><h4>Comparison between ticagrelor and clopidogrel in myocardial infarction patients with high bleeding risk- A report from the SWEDEHEART registry.</h4><i>Tjerkaski J, Jernberg T, Alfredsson J, Erlinge D, ... Venetsanos D, Szummer K</i><br /><b>Aims</b><br />Ticagrelor is associated with a lower risk of ischemic events than clopidogrel. However, it is uncertain whether the benefits of more intensive anti-ischemic therapy outweigh the risks of major bleeding in patients who have a high bleeding risk (HBR). Therefore, this study compared ticagrelor and clopidogrel in myocardial infarction (MI) patients with HBR.<br /><b>Methods and results</b><br />This study included all patients enrolled in the SWEDEHEART registry who were discharged with dual antiplatelet therapy using ticagrelor or clopidogrel following MI between 2010 and 2017. HBR was defined as a PRECISE-DAPT score ≥ 25. Information on ischemic events, major bleeding and mortality was obtained from national registries, with 365 days of follow-up. Additional outcomes include major adverse cardiovascular events (MACE), a composite of MI, stroke and all-cause mortality, and net adverse clinical events (NACE), a composite of MACE and bleeding. This study included 25,042 HBR patients, of whom 11,848 were treated with ticagrelor. Ticagrelor was associated with a lower risk of MI, stroke and MACE, but a higher risk of bleeding compared to clopidogrel. There were no significant differences in mortality and NACE. Additionally, when examining the relationship between antiplatelet therapy and bleeding risk in 69,040 MI patients, we found no statistically significant interactions between the PRECISE-DAPT score and treatment effect.<br /><b>Conclusions</b><br />We observed no difference in NACE when comparing ticagrelor and clopidogrel in HBR patients. Moreover, we found no statistically significant interactions between bleeding risk and the comparative effectiveness of clopidogrel and ticagrelor in a larger population of MI patients.<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: 01 Jun 2023; epub ahead of print</small></div>

<div><h4>A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance.</h4><i>Bigossi M, Maroteau C, Dawed AY, Taylor A, ... Palmer CNA, Siddiqui MK</i><br /><b>Background:</b><br/>and aims</b><br />The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentration of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance.<br /><b>Methods and results</b><br />A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance (general statin intolerance: ORGSI 2.42[95%CI:1.29, 4.31], p = 0.003; statin-related myopathy ORSRM 2.51[95%CI:1.28, 4.53], p = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85[95%CI:1.03, 6.65], p = 0.02). In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99 [95%CI:1.01, 3.95], p = 0.048; ORGRS 1.76 [95%CI:1.16, 2.69], p = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared to Val174Ala (general statin intolerance: HRVal174Ala 2.49 [95%CI:1.09, 5.68], p = 0.03; HRGRS 2.44 [95%CI:1.46, 4.08], p < 0.001). Finally, sequence kernel association testing (SKAT) confirmed rare variants in SLCO1B1 are associated with the risk of intolerance (p = 0.02).<br /><b>Conclusions</b><br />We provide evidence that a gene risk score based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early onset statin intolerance.<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: 30 May 2023; epub ahead of print</small></div>

<div><h4>Risk of serious hypoglycemia in patients with atrial fibrillation and diabetes concurrently taking antidiabetic drugs and oral anticoagulants: A nationwide cohort study.</h4><i>Huang HK, Liu PP, Lin SM, Yeh JI, ... Loh CH, Tu YK</i><br /><b>Aims</b><br />Evidence regarding the risks of serious hypoglycemia for patients with atrial fibrillation (AF) and diabetes mellitus (DM) taking antidiabetic medications with concurrent non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin is limited. This study aimed to investigate this knowledge gap.<br /><b>Methods and results</b><br />This retrospective cohort study used nationwide data from Taiwan\'s National Health Insurance Research Database and included a total of 56,774 adult patients treated with antidiabetic medications and oral anticoagulants between January 1, 2012 and December 31, 2020. The incidence rate ratios (IRRs) of serious hypoglycemia were estimated for patients taking antidiabetic drugs with NOACs versus warfarin. Poisson regression models with generalized estimating equations accounting for intra-individual correlation across follow-up periods were used. Stabilized inverse probability of treatment weighting was used to create treatment groups with balanced characteristics for comparisons. Compared to concurrent use of antidiabetic drugs with warfarin, those with NOACs showed a significantly lower risk of serious hypoglycemia (IRR = 0.73, 95% CI: 0.63-0.85, p<0.001). In the analyses of each NOAC, patients taking dabigatran (IRR = 0.76, 95% CI: 0.63-0.91, p = 0.002), rivaroxaban (IRR = 0.72, 95% CI: 0.61-0.86, p<0.001), and apixaban (IRR = 0.71, 95% CI: 0.57-0.89, p = 0.003) showed a significantly lower risk of serious hypoglycemia than those taking warfarin.<br /><b>Conclusion</b><br />In patients with AF and DM taking antidiabetic drugs, concurrent use of NOACs was associated with a lower risk of serious hypoglycemia than concurrent use of warfarin.<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 May 2023; epub ahead of print</small></div>

<div><h4>Heart failure pharmacological treatments and outcomes in heart failure with mildly reduced ejection fraction.</h4><i>Stolfo D, Lund LH, Sinagra G, Lindberg F, ... Rosano G, Savarese G</i><br /><b>Background</b><br />Guideline recommendations for the treatment of heart failure with mildly reduced ejection fraction (HFmrEF) derive from small subgroups in post-hoc analyses of randomized trials.<br /><b>Objectives</b><br />We investigated predictors of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI) and beta-blockers use, and the associations between these medications and mortality/morbidity in a large real-world cohort with HFmrEF.<br /><b>Methods</b><br />Patients with HFmrEF (EF 40-49%) from the Swedish HF Registry were included. The associations between medications and cardiovascular (CV) mortality/HF hospitalization (HFH) and all-cause mortality were assessed through Cox regressions in a 1:1 propensity score-matched cohort. A positive control analysis was performed in patients with EF < 40%, while a negative control outcome analysis had cancer-related hospitalization as endpoint.<br /><b>Results</b><br />Of 12 421 patients with HFmrEF, 84% received RASI/ARNI and 88% beta-blockers. Shared independent predictors of RASI/ARNI and beta-blockers use were younger age, being an outpatient, follow-up in specialty care, hypertension. In the matched cohorts, use of both RASI/ARNI and beta-blocker use was separately associated with lower risk of CV mortality/HFH (HR = 0.90, 95%CI:0.83-0.98 and HR = 0.82, 95%CI:0.74-0.90, respectively) and of all-cause mortality (HR = 0.75, 95%CI:0.69-0.81 and HR = 0.79, 95%CI:0.72-0.87, respectively). Results were consistent at the positive control analysis, and there were no associations between treatment use and the negative control outcome.<br /><b>Conclusions</b><br />RASI/ARNI and beta-blockers were extensively used in this large real-world cohort with HFmrEF. Their use was safe since associated with lower mortality and morbidity. Our findings confirm in the real world evidence from previous post-hoc analyses of trials, and represent a further call for implementing guideline recommendations.<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: 18 May 2023; epub ahead of print</small></div>

<div><h4>Sodium-Glucose Cotransporter 2 Inhibitor Use in Early-Phase Acute Coronary Syndrome with Severe Heart Failure.</h4><i>Kanaoka K, Iwanaga Y, Nakai M, Nishioka Y, ... Saito Y, Imamura T</i><br /><b>Aims</b><br />Sodium-glucose cotransporter 2 inhibitor (SGLT2i) improves clinical outcomes in patients with heart failure (HF), but has limited evidence of SGLT2i use on early-phase acute coronary syndrome (ACS). We determined association of early SGLT2i use compared with either non-SGLT2i or dipeptidyl peptidase 4 inhibitor (DPP4i) in hospitalized patients with ACS.<br /><b>Methods and results</b><br />This retrospective cohort study that used the Japanese nationwide administrative claims database included patients hospitalized with ACS aged ≥ 20 years between April 2014 and March 2021. The primary outcome was a composite of all-cause mortality or HF/ACS rehospitalization. Using 1:1 propensity score matching, the association with outcomes of the early SGLT2i use (≤14 days after admission) compared with non-SGLT2i or DPP4i was determined according to the HF treatment. Among 388 185 patients included, 115 612 and 272 573 with and without severe HF, respectively. Compared to non-SGLT2i users, the SGLT2i users had a lower hazard ratio (HR) with the primary outcome (HR: 0.83, 95% confidence interval [CI]: 0.76-0.91, p < 0.001) in the severe HF group; however, there was no significant difference in the non-severe HF group (HR: 0.92, 95% CI: 0.82-1.03, p = 0.16). SGLT2i use showed a lower risk of the outcome in patients with severe HF and diabetes compared with DPP4i (HR: 0.83, 95% CI: 0.69-1.00, p = 0.049).<br /><b>Conclusion</b><br />SGLT2i use in patients with early-phase ACS showed a lower risk of primary outcome in patients with severe HF but the effect was not apparent in patients without severe HF.<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: 12 May 2023; epub ahead of print</small></div>

<div><h4>Sodium-glucose cotransporter-2 inhibitors compared with glucagon-like-peptide-1 receptor agonists and out-of-hospital cardiac arrest in type 2 diabetes: a nationwide nested case-control study.</h4><i>Júlíusdóttir YK, Halili A, Coronel R, Folke F, ... Gislason GH, Eroglu TE</i><br /><b>Aims</b><br />Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are antidiabetic drugs that have beneficial direct effects on the myocardium by impacting cardiac ion channels and exchangers that control cardiac electrophysiology. We investigated the relationship between SGLT-2is in comparison to glucagon-like peptide-1 receptor agonists (GLP-1as) and out-of-hospital cardiac arrest (OHCA) in individuals with type 2 diabetes.<br /><b>Methods</b><br />Using data from Danish registries, we conducted a nationwide nested case-control study in a cohort of individuals with type 2 diabetes between 2013 and 2019. Cases were defined as OHCA victims from presumed cardiac causes and each case was randomly matched with five controls without OHCA based on age, sex, and index-date (OHCA date). Conditional logistic regression models were used to estimate the adjusted odds ratios (ORs) with 95% confidence interval (95% CI) of OHCA comparing SGLT-2i use with GLP-1as (reference).<br /><b>Results</b><br />The study population consisted of 3 618 OHCA cases and 18 090 matched controls. SGLT-2i was used by 91 cases and 593 controls, and was associated with reduced odds of OHCA compared with use of GLP-1a after controlling for the relevant confounders (adjusted OR 0.76 [95% CI:0.58-0.99]). The adjusted OR of OHCA associated with SGLT-2i use did not vary significantly by sex (p-value interaction: 0.461), pre-existing cardiac disease (p-value interaction: 0.762), heart failure (p-value interaction: 0.891), diabetes duration (p-value interaction: 0.101) and chronic kidney disease (p-value interaction: 0.894).<br /><b>Conclusion</b><br />Use of SGLT-2i is associated with a reduced risk of OHCA compared with use of GLP-1a in type 2 diabetes.<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: 12 May 2023; epub ahead of print</small></div>

<div><h4>New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2022.</h4><i>Tamargo J, Agewall S, Borghi C, Ceconi C, ... Kaski JC, Dobrev D</i><br /><AbstractText>Cardiovascular diseases (CVD) remain the leading cause of death worldwide and pharmacotherapy of most of them is suboptimal. Thus, there is a clear unmet clinical need to develop new pharmacological strategies with greater efficacy and better safety profiles. In this review, we summarize the most relevant advances in cardiovascular pharmacology in 2022 including the approval of first-in-class drugs that open new avenues for the treatment of obstructive hypertrophic cardiomyopathy (mavacamten), type 2 diabetes mellitus (tirzepatide), and heart failure (HF) independent of left ventricular ejection fraction (sodium-glucose cotransporter 2 inhibitors). We also dealt with fixed dose combination therapies repurposing different formulations of \"old\" drugs with well-known efficacy and safety for the treatment of patients with acute decompensated HF (acetazolamide plus loop diuretics), atherosclerotic cardiovascular disease (moderate-dose statin plus ezetimibe), Marfan syndrome (angiotensin receptor blockers plus β-blockers), and secondary cardiovascular prevention (i.e. low-dose aspirin, ramipril and atorvastatin), thereby filling existing gaps in knowledge, and opening new avenues for the treatment of CVD. Clinical trials confirming the role of dapagliflozin in patients with HF and mildly reduced or preserved ejection fraction, long-term evolocumab to reduce the risk of cardiovascular events, vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation, antibiotic prophylaxis in patients at high risk for infective endocarditis before invasive dental procedures, and vutrisiran for the treatment of hereditary transthyretin-related amyloidosis with polyneuropathy were also reviewed. Finally, we briefly discuss recent clinical trials suggesting that FXIa inhibitors may have the potential to uncouple thrombosis from hemostasis and attenuate/prevent thromboembolic events with minimal disruption of hemostasis.</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: 11 May 2023; epub ahead of print</small></div>

<div><h4>Antithrombotic treatment strategies in patients with established coronary atherosclerotic disease: 2022 joint clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), Association for Acute CardioVascular Care (ACVC) and European Association of Preventive Cardiology (EAPC).</h4><i>Valgimigli M, Aboyans V, Angiolillo D, Atar D, ... Windecker S, Fox KAA</i><br /><AbstractText>Multiple guidelines and consensus papers have addressed the role of antithrombotic strategies in patients with established coronary artery disease (CAD). Since evidence and terminology continue to evolve, the European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association for Acute Cardiovascular Care (ACVC) and European Association of Preventive Cardiology (EAPC) undertook a consensus initiative to guide clinicians to select the optimal antithrombotic regimen for each patient. The aim of this document is to provide an update for clinicians on best antithrombotic strategies in patients with established CAD, classifying each treatment option in relation to the number of antithrombotic drugs irrespective of whether the traditional mechanism of action is expected to mainly inhibit platelets or coagulation cascade. With the aim to reach comprehensiveness of available evidence, we systematically reviewed and performed meta-analyses by means of both direct and indirect comparisons to inform the present consensus document.</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: 29 Apr 2023; epub ahead of print</small></div>

<div><h4>Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines.</h4><i>Thavendiranathan P, Houbois C, Marwick TH, Kei T, ... Brezden-Masley C, Amir E</i><br /><b>Background:</b><br/>and aims</b><br />Anthracyclines can cause cancer therapy related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in LVEF in anthracycline-treated patients at increased risk for CTRCD.<br /><b>Methods</b><br />In this multicenter double-blinded, placebo-controlled trial, patients with cancer at increased risk of anthracycline-related CTRCD (per ASCO guidelines) were randomly assigned to atorvastatin 40 mg or placebo once-daily. Cardiovascular magnetic resonance (CMR) imaging was performed before and within 4 weeks-after anthracyclines. Blood biomarkers were measured at every cycle. The primary outcome was post-anthracycline LVEF, adjusted for baseline. CTRCD was defined as a fall in LVEF by > 10% to < 53%. Secondary endpoints included left ventricular (LV) volumes, CTRCD, CMR tissue characterization, high sensitivity troponin I (hsTnI), and B-type natriuretic peptide (BNP).<br /><b>Results</b><br />We randomized 112 patients (56.9 ± 13.6 years, 87 female, 73 with breast cancer): 54 to atorvastatin and 58 to placebo. Post-anthracycline CMR was performed 22 (13-27) days from last anthracycline dose. Post-anthracycline LVEF did not differ between the atorvastatin and placebo groups (57.3 ± 5.8% and 55.9 ± 7.4%, respectively) when adjusted for baseline LVEF (p = 0.34). There were no significant between-group differences in post-anthracycline LV end-diastolic (p = 0.20) or end-systolic volume (p = 0.12), CMR myocardial edema and/or fibrosis (p = 0.06 to 0.47), or peak hsTnI (p ≥ 0.99) and BNP (p = 0.23). CTRCD incidence was similar (4% versus 4%, p ≥ 0.99). There was no difference in adverse events.<br /><b>Conclusions</b><br />In patients at increased risk of CTRCD, primary prevention with atorvastatin during anthracycline therapy did not ameliorate LVEF decline, LV remodeling, CTRCD, change in serum cardiac biomarkers, or CMR myocardial tissue changes.Trial registration: NCT03186404.<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: 29 Apr 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular outcomes in hepatitis C virus infected patients treated with direct acting antiviral therapy: a retrospective multi-institutional study.</h4><i>Wu VC, Huang CH, Wang CL, Lin MH, ... Wu CS, Lin YS</i><br /><b>Background</b><br />Chronic hepatitis C virus (HCV) infection is associated with increased cardiovascular risks. We aimed to investigate the impact of direct acting antiviral (DAA) on HCV-associated cardiovascular events.<br /><b>Methods</b><br />In this retrospective cohort study, patients with the diagnosis of chronic HCV were retrieved from multi-institutional electronic medical records, where diagnosis of HCV was based on serum HCV antibody and HCV-RNA test. The patients eligible for analysis were then separated into patients with DAA treatment and patient without DAA treatment. Primary outcomes included acute coronary syndrome, heart failure (HF), venous thromboembolism (VTE), stroke, cardiovascular death, major adverse cardiovascular event (MACE), and all-cause mortality. Outcomes developed during follow-up were compared between DAA treatment and non-DAA treatment groups.<br /><b>Results</b><br />There were 41 565 patients with chronic HCV infection identified. After exclusion criteria applied, 1984 patients in the DAA treatment group and 413 patients in the non-DAA treatment group were compared for outcomes using inverse probability of treatment weighting. Compared to patients in non-DAA treatment group, patients in DAA treatment group were associated with significantly decreased HF (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.44-0.97, P = 0.035), VTE (HR: 0.19, 95% CI: 0.07-0.49, P = 0.001), MACE (HR: 0.73, 95% CI 0.59-0.92, P = 0.007), and all-cause mortality (HR: 0.50, 95% CI: 0.38-0.67, P < 0.001) at 3-year follow-up.<br /><b>Conclusions</b><br />Chronic HCV patients treated with DAA experienced lower rates of cardiovascular events and all-cause mortality than those without treatment. The reduction of VTE was the most significant impact of DAA treatment among the cardiovascular outcomes.<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: 26 Apr 2023; epub ahead of print</small></div>

<div><h4>Use of methylphenidate is associated with increased risk of out-of-hospital cardiac arrest in the general population: a nationwide nested case-control study.</h4><i>Eroglu TE, Halili A, Arulmurugananthavadivel A, Coronel R, ... Torp-Pedersen C, Gislason GH</i><br /><b>Aim</b><br />Methylphenidate, a sympathomimetic drug prescribed to treat attention-deficit/hyperactivity disorder (ADHD), is associated with cardiovascular events, but few studies have explored the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether methylphenidate use is associated with OHCA in the general population.<br /><b>Methods</b><br />Using Danish nationwide registries, we conducted a nested case-control study with OHCA-cases of presumed cardiac causes and age/sex/OHCA-date matched non-OHCA controls from the general population. Conditional logistic regression models with adjustments for well-known risk factors of OHCA were employed to estimate the odds ratio (OR) of OHCA comparing methylphenidate use with no use of methylphenidate.<br /><b>Results</b><br />The study population consisted of 46 578 OHCA-cases (median:72 years [IQR:62-81]), 68.8% men) and 232 890 matched controls. Methylphenidate was used by 80 cases and 166 controls, and was associated with increased OR of OHCA compared to non-users (OR:1.78[95%-CI:1.32-2.40]). The OR was highest in recent starters (OR≤180 days:2.59[95%-CI:1.28-5.23]). The OR of OHCA associated with methylphenidate use did not vary significantly by age (p-value interaction:0.37), sex (p-value interaction:0.94), and pre-existing cardiovascular disease (p-value interaction:0.27). Furthermore, the ORs remained elevated when we repeated the analyses in individuals without registered hospital-based ADHD (OR:1.85[95%-CI:1.34-2.55]), without severe psychiatric disorders (OR:1.98 [95%-CI:1.46-2.67]), without depression (OR:1.93: [95%-CI:1.40-2.65]), or in non-users of QT-prolonging drugs (OR:1.79[95%-CI:1.27-2.54]).<br /><b>Conclusion</b><br />Methylphenidate use is associated with an increased risk of OHCA in the general population. This increased risk applies to both sexes and is independent from age and the presence of cardiovascular disease.<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: 17 Apr 2023; epub ahead of print</small></div>

<div><h4>Vascular mechanisms of post-COVID-19 conditions: rho-kinase is a novel target for therapy.</h4><i>Sykes RA, Neves KB, Alves-Lopes R, Caputo I, ... Wood C, Berry C</i><br /><b>Background</b><br />In post-COVID-19 conditions (Long COVID), systemic vascular dysfunction is implicated but the mechanisms are uncertain, and treatment is imprecise.<br /><b>Methods</b><br />Patients convalescing after hospitalisation for COVID-19 and risk-factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated.<br /><b>Results</b><br />Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) three months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (p = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (p < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries (Masson\'s Trichrome (MT) 69.7% [95%CI: 67.8, 71.7]; picrosirius red 68.6% [95% CI: 64.4, 72.8]) versus controls (MT 64.9% [95%CI:59.4, 70.3] [p = 0.028]; picrosirius red 60.1% [95% CI: 55.4, 64.8], [p = 0.029]). Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9, 49.3) vs. controls (10.0%; 95% CI: 4.4, 15.6) (p < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated.<br /><b>Conclusion</b><br />Patients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials.<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: 05 Apr 2023; epub ahead of print</small></div>

<div><h4>Impact of body mass on P2Y12-inhibitor de-escalation in acute coronary syndromes-a substudy of the TROPICAL-ACS trial.</h4><i>Komócsi A, Merkely B, Hadamitzky M, Massberg S, ... Sibbing D, Aradi D</i><br /><b>Aims</b><br />Clinical guidelines recommend de-escalation antiplatelet strategies to reduce bleeding risk in acute coronary syndrome (ACS) patients, albeit with a weak recommendation. This sub-study of the TROPICAL-ACS trial aimed to determine the impact of body mass on the efficacy of platelet-function testing-guided de-escalation regimen in ACS patients after PCI.<br /><b>Methods and results</b><br />Patients were randomized to prasugrel (control group) or a platelet-function testing-guided regimen with clopidogrel or prasugrel defined after one-week clopidogrel. The primary endpoint was the net clinical benefit (cardiovascular death, myocardial infarction, stroke, or BARC 2-5 bleeding) for 12 months. Overweight was defined as a body mass index (BMI) >25 kg/m2.Patients without overweight showed a significant net clinical benefit from the de-escalation strategy while in overweight cases de-escalation was comparable to prasugrel treatment (HR: 0.52; 95% CI: 0.31-0.88; p = 0.013, and HR: 0.95; 95%CI: 0.69-1.31, p = 0.717, p-non-inferiority = 0.03, respectively, p-interaction = 0.053). The benefit of de-escalation in terms of the risk of bleeding or of the ischemic events did not reach statistical significance. Bleeding events with de-escalation were less frequent in non-overweight patients but comparable in overweight patients (HR: 0.55; 95% CI: 0.30-1.03; p = 0.057, and HR: 0.95; 95% CI: 0.64-1.41, respectively p-interaction = 0.147). Non-overweight patients had lower ischemic event rates with de-escalation, while overweight cases had slightly less. (HR: 0.47; 95%CI: 0.18-1.25, p = 0.128, and HR: 0.89; 95% CI: 0.53-1.50, respectively p-interaction = 0.261).<br /><b>Conclusions</b><br />The strategy of guided DAPT de-escalation was associated with a significant net clinical benefit in non-overweight patients, while the two strategies were equivalent in overweight patients.<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: 04 Apr 2023; epub ahead of print</small></div>

<div><h4>The efficacy of PCSK9 inhibitors on major cardiovascular events and lipid profile in patients with diabetes: a systematic review and meta-analysis of randomized controlled trials.</h4><i>Imbalzano E, Ilardi F, Orlando L, Pintaudi B, Savarese G, Rosano G</i><br /><b>Objective</b><br />To evaluate the specific effects of PCSK9 inhibitors (i.e. alirocumab and evolocumab) on major cardiovascular events (MACE) and lipid profile in patients with diabetes.<br /><b>Methods</b><br />We conducted a systematic review of literature according to the PRISMA statement. A total of 8 randomized control trials (RCTs) enrolling 20 651 patients with diabetes were included. Mean follow-up was 51 weeks. We included RCTs which had compared the PCSK9i alirocumab and evolocumab with placebo in subjects with hypercholesterolemia and diabetes mellitus.<br /><b>Results</b><br />MACE occurred in 8.7% of patients with diabetes randomized to PCSK9i vs.11.0% of those randomized to placebo. Thus, the use of alirocumab or evolocumab reduced MACE by 18% (relative risk [RR] 0.82, 95% confidence interval [CI] 0.74-0.90). Compared to control group, the use of PCSK9 inhibitors was associated with a significant % change from baseline in LDL-C (mean difference [MD]-58.48%; 95% CI: -63.73 to -53.22%), P < 0.0001), HDL-C (MD5.21%; 95% CI: 3.26 to 7.17%), Triglycerides (MD-14.59%; 95% CI: -19.42 to -9.76%), non-HDL-C (MD -48.84%; 95% CI: -54.54 to -43.14%) and total Cholesterol (MD-33.76%; 95% CI: -38.71 to -28.8%). Moreover, a significant reduction of Lp(a) (MD-32.90%; 95% CI: -38.55 to -27.24%)and ApoB (MD-46.83%; 95% CI: -52.71 to -40.94%)were observed in PCSK9i group compared to placebo.<br /><b>Conclusions</b><br />PCSK9i appear to be effective in reducing the risk of MACE and in improving lipid profiles of subjects with diabetes and dyslipidemia.<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: 27 Mar 2023; epub ahead of print</small></div>

<div><h4>The neurocognitive effects of atrial fibrillation: benefits of the ABC pathway.</h4><i>Calvert P, Gupta D, Lip GYH</i><br /><AbstractText>Atrial fibrillation has a recognised association with not only stroke, but also neurocognitive impairment and both vascular and Alzheimer\'s dementia. Effective management of atrial fibrillation can reduce the risk of such complications. In this narrative review article, we discuss the pathophysiological links between atrial fibrillation and dementia, as well as the benefits of adherence to the guideline-recommended \'ABC\' Pathway.</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: 25 Mar 2023; epub ahead of print</small></div>

<div><h4>Impact of the Antiplatelet Strategy Following Patent Foramen Ovale Percutaneous Closure.</h4><i>Guedeney P, Farjat-Pasos JI, Asslo G, Roule V, ... Rodés-Cabau J, AIR-FORCE group</i><br /><b>Aims</b><br />Temporary dual antiplatelet therapy (DAPT) is recommended following patent foramen ovale (PFO) percutaneous closure although its benefit, compared to single antiplatelet therapy (SAPT), has not been demonstrated in this setting. We aimed at assessing outcomes following PFO closure according to the antiplatelet strategy at discharge.<br /><b>Methods and results</b><br />The ambispective AIR-FORCE cohort included consecutive patients from 7 centers in France and Canada undergoing PFO closure and discharged without anticoagulation. Patients treated in French and Canadian centers were mostly discharged with DAPT and SAPT, respectively. The primary endpoint was the composite of death, stroke, transient ischemic attack, peripheral embolism, myocardial infarction, or BARC type ≥2 bleeding with up to 5 years of follow-up. The impact of the antiplatelet strategy on outcomes was evaluated with a marginal Cox model (cluster analyses per country) with inverse probability weighting according to propensity score. A total of 1,532 patients (42.2% female, median age: 49 [40-57] years) were included from 2001 to 2022, of whom 599 (39.1%) were discharged with SAPT and 933 (60.9%) with DAPT, for ≤3 months in 894/923 (96.9%) cases. After a median follow-up of 2.4[1.1-4.4] years, a total of 58 events were observed. In the weighted analysis the rate of the primary endpoint up to 5 years was 7.8% in the SAPT strategy and 7.3% in the DAPT strategy (weighted hazard ratio 1.04, 95% confidence interval 0.59-1.83).<br /><b>Conclusion</b><br />The antiplatelet strategy following PFO closure did not seem to impact clinical outcomes, thus challenging the current recommendations of temporary DAPT.<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: 24 Mar 2023; epub ahead of print</small></div>

<div><h4>High- vs. low-dose diclofenac and cardiovascular risks: a target trial emulation.</h4><i>Schmidt M, Arendt-Nielsen L, Hauge EM, Sørensen HT, Pedersen L</i><br /><b>Aims</b><br />To examine the dose-dependency of diclofenac\'s cardiovascular risks.<br /><b>Methods and results</b><br />Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent NSAID prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3,789,617), diclofenac initiators (n = 1,894,834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12).<br /><b>Conclusions</b><br />Initiators of high- and low-dose diclofenac had comparable increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral.<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: 15 Mar 2023; epub ahead of print</small></div>

<div><h4>Sex-based differences in risk of ischemic stroke or systemic embolism after BNT162b2 or CoronaVac COVID-19 vaccination in patients with atrial fibrillation: A self-controlled case series and nested case-control study.</h4><i>Ye X, Huang C, Yan VKC, Kang W, ... Wong ICK, Chan EW</i><br /><b>Aims</b><br />Patients with atrial fibrillation (AF) have a higher risk of ischemic stroke or systemic embolism with a greater risk for female patients. This study aims to evaluate the risk of ischemic stroke or systemic embolism and bleeding following COVID-19 vaccination in patients with AF and the sex differences.<br /><b>Methods and results</b><br />Self-controlled case series (SCCS) analysis was conducted to evaluate the risk of ischemic stroke or systemic embolism and bleeding following BNT162b2 or CoronaVac in patients with AF, using the territory-wide electronic medical records from the Hospital Authority and vaccination records from the Department of Health in Hong Kong. Patients with a primary diagnosis of ischemic stroke or systemic embolism or bleeding in the inpatient setting between February 23, 2021 and March 31, 2022 were included. A nested case-control analysis was also conducted with each case randomly matched with ten controls according to sex, age, Charlson comorbidity index and date of hospital admission. Conditional Poisson regression was used in the SCCS analysis and conditional logistic regression was used in nested case-control analysis to assess the risks and all analyses were stratified by sex and type of vaccines. Among 51 158 patients with AF, we identified an increased risk of ischemic stroke or systemic embolism after the first dose of BNT162b2 in SCCS analysis during 0-13 days (incidence rate ratio 6.60[95% CI 1.51-28.77]) and 14-27 days (6.53[95% CI 1.31-32.51]), and nested case-control analysis during 0-13 days (adjusted odds ratio 6.21 [95% CI 1.14-33.91]) and 14-27 days (5.52 [95% CI 1.12-27.26]) only in female patients. The increased risk in female patients following the first dose of CoronaVac was only detected during 0-13 days (3.88 [95% CI 1.67-9.03]) in the nested case-control analysis. No increased risk of ischemic stroke or systemic embolism was identified in male patients and no increased risk of bleeding was detected in all patients with AF for both vaccines. An increased risk of ischemic stroke or systemic embolism after COVID-19 was also observed in both females (17.42 [95% CI 5.08-59.73]) and males (6.63 [95% CI 2.02-21.79]).<br /><b>Conclusions</b><br />The risk of ischemic stroke or systemic embolism after COVID-19 vaccination was only increased in female patients with AF. However, as the risk after COVID-19 was even higher, proactive uptake of COVID-19 vaccines is recommended to prevent the potential severe outcomes after infection.<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: 14 Mar 2023; epub ahead of print</small></div>

<div><h4>Within and beyond 12-month efficacy and safety of antithrombotic strategies in patients with established coronary artery disease. Two companion network meta-analyses of the 2022 joint clinical consensus statement of the European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association for Acute CardioVascular Care (ACVC) and European Association of Preventive Cardiology (EAPC).</h4><i>Navarese EP, Landi A, Oliva A, Piccolo R, ... Windecker S, Valgimigli M</i><br /><b>Aims</b><br />To appraise all available antithrombotic treatments within or after 12 months following coronary revascularization and/or acute coronary syndrome in two network meta-analyses (NMA).<br /><b>Methods and results</b><br />Forty-three (N = 189 261) trials within 12 months and 19 (N = 139 086 patients) trials beyond 12 months were included for efficacy/safety endpoints appraisal.Within 12 months, ticagrelor 90 mg bis in die (b.i.d.) (hazard ratio [HR] 0.66; 95% confidence interval [CI]: 0.49-0.88), aspirin and ticagrelor 90 mg (HR 0.85; 95%CI: 0.76-0.95), or aspirin, clopidogrel and rivaroxaban 2.5 mg b.i.d. (HR 0.66; 95%CI: 0.51-0.86) were the only treatments associated with lower cardiovascular mortality, compared with aspirin and clopidogrel, without or with greater bleeding risk for the first and the other treatment options, respectively.Beyond 12 months, no strategy lowered mortality; compared with aspirin; the greatest reductions of myocardial infarction (MI) were found with aspirin and clopidogrel (HR 0.68; 95%CI, 0.55-0.85) or P2Y12 inhibitor monotherapy (HR 0.76; 95%CI, 0.61-0.95), especially ticagrelor 90 mg (HR 0.54; 95%CI, 0.32-0.92), and of stroke with VKA (HR, 0.56; 95%CI, 0.44-0.76) or aspirin and rivaroxaban 2.5 mg (HR, 0.58; 95%CI, 0.44-0.76). All treatments increased bleeding except P2Y12 monotherapy, compared with aspirin.<br /><b>Conclusion</b><br />Within 12 months, ticagrelor 90 mg monotherapy was the only treatment associated with lower mortality, without bleeding risk trade-off compared with aspirin and clopidogrel. Beyond 12 months, P2Y12 monotherapy, especially ticagrelor 90 mg, was associated with lower MI without bleeding trade-off; aspirin and rivaroxaban 2.5 mg most effectively reduced stroke, with a more acceptable bleeding risk than VKA, compared with aspirin. Registration URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifiers: CRD42021243985 and CRD42021252398.<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 Mar 2023; epub ahead of print</small></div>