bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of alirocumab added to high-intensity statin therapy on platelet function in AMI patients: a pre-specified substudy of the randomized, placebo-controlled PACMAN-AMI trial
Authors: Ueki Y , Haner J , Losdat S , Gargiulo G , Bar S , Otsuka T , Kavaliauskaite R , Mitter V , Temperli F , Shibutani H , Siontis G , Valgimigli M , Windecker S , Koskinas K , Raber L 
Published: October 2022

Abstract

Background
Previous small observational studies have suggested a potential association of proprotein convertase subtilisin kexin type 9 (PCSK9) and platelet reactivity. However, the role of the PCSK9 inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown.

Purpose
We investigated the effect of alirocumab on P2Y12 reaction unit (PRU) on top of high-intensity statin therapy among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel).

Methods
This was a pre-specified, powered, pharmacodynamic substudy nested within the PACMAN (effects of the PSCK9 antibody AliroCuMab on coronary Atherosclerosis in patieNts with Acute Myocardial Infarction) trial, a randomized, double-blind trial comparing biweekly alirocumab (150mg) versus placebo in AMI patients undergoing percutaneous coronary intervention (PCI). Patients recruited at Bern University Hospital, receiving DAPT with either ticagrelor or prasugrel at 4 weeks and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The VerifyNow P2Y12 point-of-care assays were used to measure PRU at baseline (i.e. before first study drug administration), 4 weeks, and 52 weeks after study drug administration (higher PRU levels indicating greater platelet aggregation). The primary endpoint was PRU at 4 weeks.

Results
Among 139 randomized patients (mean age 58.2 years [SD, 9.5], 21 [15.0%] women, mean LDL-C level 150.6mg/dL [SD, 30.9]), baseline characteristics were well balanced between groups including baseline PRU (50.0 [IQR, 120.0] in the alirocumab group vs. 62.0 [IQR, 122.0] in the placebo group, P=0.75). At 4 weeks, mean LDL-C was significantly lower in the alirocumab group (23.5 [SD, 23.7] mg/dL vs. 74.4 [SD, 30.5] mg/dL, P&lt;0.001). The majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] vs. 69 [94.5%], P=0.14). There were no significant differences in PRU at 4 weeks (12.5 [IQR, 27.0] vs. 19.0 [IQR, 30.0], P=0.26) and at 52 weeks (25.0 [IQR, 37.0] vs. 34.0 [IQR, 59.0], P=0.07) (Figure). Consistent results were observed in 126 patients treated with ticagrelor (i.e. after excluding 13 patients treated with prasugrel) at 4 weeks (13.0 [IQR, 20.0] vs. 18.0 [IQR, 27.0], P=0.28).

Conclusion
Among AMI patients receiving DAPT with potent P2Y12 inhibitors, alirocumab had no significant effect on platelet function as assessed by PRU.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): Bern University Hospital
Perioperative rosuvastatin therapy increases creatine kinase and the risk of acute kidney injury in patients undergoing cardiac surgery
Authors: Wijesurendra R , Sardell R , Hill M , Jayaram R , Samuel N , Staplin N , Emberson J , Collins R , Zheng Z , Haynes R , Casadei B 
Published: October 2022

Abstract

Introduction
In patients undergoing cardiac surgery, perioperative statin therapy does not prevent atrial fibrillation or myocardial injury, but results in increased creatinine levels after surgery. Here we investigated the incidence of acute kidney injury (AKI) in 1922 patients scheduled for elective cardiac surgery who were randomized to perioperative rosuvastatin (20 mg once daily) or placebo in the Statin Therapy In Cardiac Surgery (STICS) trial.

Methods
AKI post-surgery was defined according to international guidelines using plasma creatinine. Biomarkers related to kidney function, muscle injury and inflammation were investigated, including cystatin C, total creatine kinase (CK), troponin I, growth differentiation factor 15 (GDF-15), interleukin-6 (IL-6), procalcitonin, and placental growth factor (PGF).

Results
At 48 hours post-surgery, AKI was significantly more common in patients allocated to rosuvastatin compared to placebo when defined by creatinine (24.7% vs 19.3%; OR 1.37 [95% CI 1.10–1.70]; p=0.005; Figure 1A) or by cystatin C (9.2% vs 5.1%; OR 1.86 [95% CI 1.29–2.67]; p&lt;0.001; Figure 1B). Elevations in CK to &gt;10x and &gt;40x baseline level were also more frequent in rosuvastatin-allocated patients compared to placebo (30.9% vs 26.5%, p=0.02, and 2.1% vs 0.7%, p=0.02, respectively; Figure 1C). Post-operative concentrations of troponin I, GDF-15, IL-6, procalcitonin, and PGF were similar between the groups (Table 1).

Conclusions
Perioperative rosuvastatin initiation increased the absolute risk of AKI after cardiac surgery by 4–5%. Rosuvastatin also led to greater elevations in post-operative creatine kinase, but did not affect other biomarkers of tissue injury, inflammation, and myocardial injury. Further research is needed to delineate the underlying mechanism of AKI with perioperative rosuvastatin.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation
Statin therapy in children with familial hypercholesterolemia: a meta-analysis
Authors: Lewek J , Surma S , Bytyci I , Banach M 
Published: October 2022

Abstract

Background
Familial hypercholesterolemia (FH) is a genetic disorder that may develop serious vascular damage leading to a high risk of the development of premature of cardiovascular disease (CVD).

Purpose
The aim of this meta-analysis was to evaluate the efficacy of statins on lipid profile in children patients with diagnosed FH.

Methods
We systematically searched selected electronic databases from inception until 15th March 2022. Main endpoints were lipid profile: total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and apolipoprotein B (Apo-B), lipoprotein(a) (Lp(a)). Random effects mean reduction were used to evaluate the efficacy of statins.

Results
Eight randomized controlled trial (RCTs) with a total of 1025 children patients with FH (statins n=529) were included in the meta-analysis. At mean follow-up was 10.4 months. We showed that in the group of children treated with statins, compared to control, higher mean TC reduction −1.95 mmol/L (−75 mg/dL) [95% CI, −1.36 to −2.54; p&lt;0.001], TG reduction −0.13 mmol/L (−11.5 mg/dL) [−0.04 to −0.23; p&lt;0.001], and LDL-C reduction −1.94 mmol/L (−75 mg/dL) [−1.43 to −2.45; p&lt;0.001] were observed with significantly higher increase of the mean HDL-C, 0.37 mmol/L (14.3 mg/dL) [0.04 to 0.69; p=0.03] (Figure 1). In addition, the statins significantly reduced Apo-B [−0.50 g/L; p&lt;0.001] and did not significantly affect Lp(a) [0.13 mg/dL; p=0.87] in statins group (Figure 2).

Conclusions
The results of our meta-analysis clearly showed that children treated with statin therapy had significantly improved lipid profile with lack of effect on Lp(a). This data might help to improve statin therapy in FH children, which is highly underused worldwide.

Funding Acknowledgement
Type of funding sources: None.
Lower risk of gout in sodium glucose cotransporter 2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors in type-2 diabetes patients: a propensity score-matched study
Authors: Chou O H I , Liu X , Zhou J , Jing F , Li L , Lee S , Wong W T , Zhang Q , Chang C , Liu T , Tse G , Cheung B M Y 
Published: October 2022

Abstract

Background
The effects of sodium-glucose cotransporter 2 inhibitors (SGLT2I) versus dipeptidyl peptidase-4 inhibitors (DPP4I) on the risk of new gout diagnosis have not been explored. This study aims to compare the effects of SGLT2I against DPP4I on gout risks in a Chinese population.

Methods
This was a retrospective population-based cohort study of patients with type-2 diabetes mellitus treated with SGLT2I or DPP4I between January 1st, 2015 and December 31st, 2020 in Hong Kong. The study outcomes are new-onset gout and all-cause mortality. Propensity score matching (1:1 ratio) between SGLT2I and DPP4I was performed. Univariable and multivariable Cox regression analysis models were conducted. Competing risks models and multiple approaches based on the propensity score were applied.

Patients
This study included 60996 patients (median age: 62.3 years old, 54.96% males; SGLTI group: n=21690; DPP4I group: n=39306).

Results
In the matched cohort, 1096 developed gout (IR: 2.52%) and 2195 died (IR: 5.05%). Univariable Cox regression showed that SGLT2I use was associated with lower risks of new diagnosis of gout (hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.30–0.39; P-value&lt;0.0001) and all-cause mortality (HR: 0.35; 95% CI: 0.32–0.39; P-value&lt;0.0001) compared to DPP4I. The associated remained for both new diagnosis of gout (HR: 0.46; 95% CI: 0.37–0.57; P-value&lt;0.0001) and all-cause mortality (HR: 0.38; 95% CI: 0.33–0.44; P-value&lt;0.0001) after adjusting for significant demographics, past comorbidities, and non-SGLT2I/DPP4I medications. The risks of gout were lowered in each types of SGLT2I. The results were consistent on competing risk and other propensity score approaches analyses.

Conclusions
SGLT2I use was associated with lower risks of new gout diagnosis compared to DPP4I use.

Funding Acknowledgement
Type of funding sources: None.
The DPP4 inhibitor linagliptin exacerbated heart failure due to energy deficiency via downregulation of glucose absorption and utilization in mice
Authors: Shiraki A , Oyama J , Shimizu T , Node N 
Published: October 2022

Abstract

Background
It was reported that glucagon-like peptide-1 has cardio-protective effects, however, the occurrence of heart failure was increased with DPP4 inhibitor in some large clinical trials.

Purpose
The purpose of the present work was to clarify whether DPP4 inhibitor had any effects on chronic, dilated heart failure and to identify the mechanisms.

Methods
Heart / Muscle-specific Manganese superoxide dismutase (Mn-SOD)-deficient mice, (H/M-Sod−/−) which exert dilated cardiomyopathy were randomized to receive low dose (1 mg/kg) linagliptin, HF-L group; high dose (10 mg/kg) linagliptin, HF-H group; mixed with food, or normal food, HF group; for eight weeks. Then, evaluation was performed in cardiac function and pathophysiological changes.

Result
Interestingly, the mice treated with linagliptin treatment exhibited shorter life span and greater heart/body weight ratio. Echocardiographic studies showed decreased contractility in the HF-H group with compared to the HF control group. In Sirius Red staining, severer fibrosis was also observed in the linagliptin groups. HbA1c levels did not change among three groups, however, glycogen content in the liver was significantly decreased in the linagliptin groups. Similarly, indirect calorimetry showed decreased carbohydrate consumption in the HF-H group compared to the HF control group, suggesting worsening of heart failure was due to unavailability of carbohydrates as an energy source. Therefore, we fed a diet containing 33 wt% glucose to the HF-H group as complementary experiments. As a result, adequate glucose supplementation reduced cardiac fibrosis and cardiac function, while worsened life span, HbA1c levels and CHO consumption were not changed. Therefore, we hypothesized that there might be a change in the absorption of glucose in intestine or utilization ability of glucose in body another experiments were performed. 13C, which was released from mice after the oral administration of 13C glucose and measured by respiratory gas analysis, was significantly reduced in HF-H mice. The measurements the amount of 13C in feces revealed increased levels of unabsorbed glucose by linagliptin treatment in HF. In addition, GLUT2, a glucose transporter, in small intestine, was downregulated in the HF-H and the HF-HG groups. On the other hand, the cardiac uptake of Deoxy-D-glucose, 2-[1,2-3H(N)] (3H-2DG), which was injected from mice tail vein, was not different between in the HF-H group and in the HF control group. Taken together, linagliptin treatment may inhibit glucose transport in intestine in HF.

Conclusions
Linagliptin treatment exacerbated heart failure, resulting in shortened life span, worsened cardiac function, and fibrosis of the myocardium. DPP4 inhibitor may promote the cardiac cachexia and exacerbate heart failure at least, in part, through modification of glucose absorption and utilization.

Funding Acknowledgement
Type of funding sources: None.
Anti-inflammatory potential of SGLT2 inhibitors: a systematic review and meta-analysis of preclinical studies in rodents
Authors: Theofilis P , Sagris M , Oikonomou E , Antonopoulos A S , Siasos G , Tsioufis K , Tousoulis D 
Published: October 2022

Abstract

Background
Sodium-glucose cotransporter-2 (SGLT2) inhibition is at the forefront of scientific research due to their astonishing effect in ameliorating the prognosis of cardiorenal diseases. Several mechanisms have been proposed for these pleiotropic effects, including anti-inflammatory ones.

Purpose
Our systematic review and meta-analysis aimed to assess the effect of SGLT2 inhibitors on inflammatory markers in experimental rodent models.

Methods
We conducted a literature search to detect studies examining the effect of SGLT2 inhibitors on inflammatory markers [interleukin-6 (IL-6), C reactive protein (CRP), tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1 (MCP1)] in rodent animal models. Consequently, a meta-analysis of the included studies was performed, assessing the differences in the levels of the inflammatory markers between the treatment and the control group as its primary outcome. Studies not reporting in vivo experiments on mice/rats or not measuring inflammatory markers in the plasma or serum were excluded. Moreover, studies not administering SGLT2 inhibitors as treatment or simultaneously utilizing SGLT2 inhibitors with other treatment were further excluded. Effect sizes were pooled via random-effect model and results are expressed as standardized mean difference (SMD) with 95% confidence intervals (CIs). Correction for small-sample bias was also applied with the use of Hedge's g. I2 was chosen as the measure of between-studies heterogeneity.

Results
The systematic literature review yielded 30 studies whose meta-analysis suggested that treatment with an SGLT2 inhibitor resulted in decreases of IL-6 [standardized mean difference (SMD): −1.49, 95% CI −2.00 to −0.99, I2: 71%), CRP (SMD: −2.17, 95% CI −2.80 to −1.53, I2: 64%), TNF-α (SMD: −1.68, 95% CI −2.05 to −1.31, I2: 38%), and MCP1 (SMD: −2.04, 95% CI −2.91 to −1.17, I2: 66%) (Figure 1). The effect was of lesser magnitude in cases of empagliflozin use (p for interaction=0.03 to 0.05). Possible publication bias was noted in the case of IL-6 and CRP. The findings remained largely unaffected after the sensitivity analyses and the exclusion of outlying studies.

Conclusion
The present meta-analysis suggests that SGLT2 inhibition results in reduction of inflammatory markers in rodents, suggesting an anti-inflammatory mechanism of action

Funding Acknowledgement
Type of funding sources: None.
Characterization of the SGLT2 interaction network and its regulation by SGLT2 inhibitors: a bioinformatic analysis
Authors: Wicik Z , Nowak A , Jarosz-Popek J , Wolska M , Eyileten C , Siller-Matula J , Von Lewinski D , Sourij H , Postula M 
Published: October 2022

Abstract

Background
SGLT2 (Solute Carrier Family 5 Member 2, SLC5A2) is a promising target of a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Rising evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart, endothelial cells, liver, adipose tissue. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with its binding force, location of their targets in the SGLT2 networks, target involvement in signaling pathways, and their tissue-specific expression.

Methods
Thus to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms (Autophagy, Oxidative stress, Aging, Senescence, Inflammation, AMPK pathways, mTOR pathways) which seems to be crucial to elucidate SGLT2 role in a variety of clinical manifestations.

Results
Our analysis focused on selected organs using the TISSUES database identified in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery showed the highest expression confidence of SGLT2 and its network components. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, Dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. Shortest paths analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were ADIPOQ, INS, GLUT4, ACE, and GLUT1, but also less recognized ILK, ADCY7. Among interactors not associated with key-terms, but which appeared in multiple shortest-paths analyzes were GPT, COG2 and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1) and cancer-related terms.

Conclusion
This study provides comprehensive and ranked information regarding the SGLT2 interaction network in the context of tissue expression and might be helpful to predict the clinical effects of the most commonly used SGLT2i.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agencja badań medycznych - grant number 2019/ABM/01/00037Medical University of Warsaw - grant number 1M9/2/M/MG/N/21
Combined anticoagulant and antiplatelet therapy is associated with an improved outcome in hospitalised patients with COVID-19: a propensity matched cohort study
Authors: Matli K , Chamoun N , Fares A , Zibara V , Al-Osta S , Nasrallah R , Salameh P , Mokhbat J , Ghanem G 
Published: October 2022

Abstract

Background
COVID-19 is a respiratory disease that results in a prothrombotic state manifesting as thrombotic, microthrombotic and thromboembolic events. As a result, several antithrombotic modalities have been implicated in the treatment of this disease.

Purpose
Currently, prophylactic dose anticoagulation is considered the standard of care antithrombotic regimen in hospitalised patients with COVID-19. However, high-quality data about the subject is unavailable. This study aimed to identify if therapeutic anticoagulation (TAC) or concurrent use of antiplatelet and anticoagulants was associated with an improved outcome in this patient population.

Methods
A retrospective observational cohort study of adult patients admitted to a single university hospital for COVID-19 infection was performed. The primary outcome was a composite of in-hospital mortality, intensive care unit (ICU) admission or the need for mechanical ventilation. The secondary outcomes were each of the components of the primary outcome, in-hospital mortality, ICU admission, or the need for mechanical ventilation.

Results
242 patients were included in the study and divided into four subgroups: Therapeutic anticoagulation (TAC), prophylactic anticoagulation+antiplatelet (PACAP), TAC+antiplatelet (TACAP) and prophylactic anticoagulation (PAC) which was the reference for comparison. Multivariable Cox regression analysis and propensity matching were done and showed when compared with PAC, TACAP and TAC were associated with less in-hospital all-cause mortality with an adjusted HR (aHR) of 0.113 (95% CI 0.028 to 0.449) and 0.126 (95% CI 0.028 to 0.528), respectively. The number needed to treat in both subgroups was 11. Furthermore, PACAP was associated with a reduced risk of invasive mechanical ventilation with an aHR of 0.07 (95% CI 0.014 to 0.351). However, the was no statistically significant difference in the occurrence of major or minor bleeds, ICU admission or the composite outcome of in-hospital mortality, ICU admission or the need for mechanical ventilation.

Conclusion
The use of combined anticoagulant and antiplatelet agents or TAC alone in hospitalised patients with COVID-19 was associated with a better outcome in comparison to PAC alone without an increase in the risk of major and minor bleeds. Sufficiently powered randomised controlled trials are needed to further evaluate the safety and efficacy of combining antiplatelet and anticoagulants agents or using TAC in the management of patients with COVID-19 infection.

Funding Acknowledgement
Type of funding sources: None.
Reduced dose, but not reduced risk: rates of inappropriate apixaban dose reduction and stroke and bleeding incidence
Authors: Harrington J , Arps K , Wu A , Carnicelli A P , Chiswell K , Chrischilles E , Shantha G , Vanwormer J , Mundl H , Viethan T , Alexander J H , Lopes R D , Washam J , Patel M R 
Published: October 2022

Abstract

Introduction
Patients with atrial fibrillation (AF) should be prescribed standard-dose (5mg twice daily) apixaban for stroke prevention unless they meet 2 or more criteria: age ≥80, weight ≤60kg, and/or creatinine ≤1.5mg/dL, in which case a reduced-dose (2.5mg twice daily) is indicated. Despite this, some clinicians may also prescribe reduced-dose apixaban to patients who do not meet criteria for dose reduction, in an effort to reduce bleeding risk.

Purpose
To assess apixaban prescribing patterns in patients with AF based on dose reduction criteria and to characterize baseline demographics and incidence of ischemic stroke, major bleeding, and intracranial hemorrhage (ICH) for patients stratified by standard-dose, appropriately reduced-dose, and inappropriately reduced-dose apixaban.

Methods
Using pooled data from 8 large hospitals in PCORnet, a multicenter national healthcare research network, we assessed the standard and reduced-dose apixaban prescribing patterns for patients with AF, with additional stratification of patients prescribed 2.5mg based on presence or absence of 2+ criteria for dose reduction. We then assessed baseline characteristics and 5-year event rate of ischemic stroke, major bleeding, ICH and death.

Results
Of 45,947 patients with AF on apixaban and available dosing information, 38,861 (85%) were prescribed apixaban 5mg and 7086 (15%) were prescribed 2.5mg. Of patients prescribed apixaban 2.5mg, 4321 (61%) did not meet criteria for dose reduction. Patients on reduced dose apixaban were more likely to be female and have comorbidities such as heart failure, hypertension, and prior ischemic stroke. These trends were more pronounced for patients meeting dose adjustment criteria than those not meeting criteria (Table 1).
Unadjusted analyses found patients on 2.5mg of apixaban were significantly more likely to experience ischemic stroke, major bleeding, and all-cause death. Patients with 2+ dose reduction criteria on 2.5mg of apixaban had the highest rates of each event, but patients who were prescribed reduced dose without meeting criteria were also at elevated risk (Table 2).

Conclusion
Many patients prescribed reduced-dose apixaban do not meet criteria for dose reduction. Because patients prescribed reduced dose apixaban are older and have more cardiovascular risk factors, their incidence of stroke, major bleeding, and death exceeds that of full dose treated patients. These risks exist both for patients who do and do not meet criteria for dose reduction, suggesting potential under-treatment for the majority of dose-reduced patients.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Bayer