bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of sodium-glucose cotransporter-2 (SGLT2) inhibitors to reduce cardiovascular and renal outcomes: a network meta-analysis of randomized controlled trials
Authors: Kani R , Watanabe A , Miyamoto Y , Kuno T 
Published: November 2023

Abstract

Background
Although the cardio- and reno-protective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established, the differences across agents in various populations have yet to be elucidated.

Purpose
To investigate the profiles of each SGLT2 inhibitor in patients from various backgrounds.

Methods
MEDLINE and EMBASE databases were searched in November 2022 to identify randomized controlled trials (RCTs) comparing SGLT2 inhibitor to placebo. To compare each SGLT2 inhibitor, a network meta-analysis was performed. The primary efficacy endpoint was the composite of cardiovascular (CV) mortality and hospitalisations for heart failure (HHF). The secondary efficacy endpoints were all-cause mortality, CV mortality, HHF, kidney disease progression, and acute kidney injury (AKI). We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease (CKD). Safety endpoints were also assessed between SGLT2 inhibitors in all cohorts.

Results
This study included 19 RCTs with a total of 94,495 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. Although there were consistent tendencies favouring SGLT2 inhibitors over placebo, no significant difference between SGLT2 inhibitors was manifested for the primary outcome (Figures 1-2). Compared to placebo, empagliflozin and dapagliflozin improved all studied efficacy outcomes in overall population and demonstrated consistent benefits on reduction in primary outcome, HHF, kidney disease progression, and AKI independent of diabetic status. Among patients without CKD, empagliflozin were associated with lower risks of the primary outcome compared to ertugliflozin (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.60-0.98), CV mortality compared to canagliflozin (HR, 0.62; 95% CI, 0.40-0.96) and dapagliflozin (HR, 0.59; 95%CI, 0.39-0.89), and all-cause mortality compared to dapagliflozin (HR, 0.72; 95% CI, 0.52-0.99). All SGLT2 inhibitors increased the occurrence of genital infections. As compared to a placebo, canagliflozin increased the risks of limb amputation (HR, 1.58; 95% CI 1.07-2.35) and fracture (HR, 1.19; 95%CI 1.01-1.40).

Conclusions
SGLT2 inhibitors have comparable efficacy profiles in reducing cardiovascular and renal events. Whilst empagliflozin and dapagliflozin are beneficial even in patients without diabetes, empagliflozin may be an especially reasonable opiton in patients without CKD.Figure 1Figure 2
Empagliflozin in patients with myocardial infarction: an updated meta-analysis
Authors: Abouzid M , Al-Dardery N M , Ghaith H S , Khitiy H , Khaity A 
Published: November 2023

Abstract

Background/Introduction
Empagliflozin is one of the sodium-glucose cotransporter 2 (SGLT2) inhibitors that is used to treat type 2 diabetes and has recently been studied for its potential benefits in patients with myocardial infarction.

Purpose
We performed this meta-analysis to update the present evidence about the safety and efficacy of empagliflozin in patients with myocardial infarction.

Methods
We searched PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials (RCTs) from inception until February 2023. Records were screened for eligible studies, and all relevant outcomes were pooled as mean difference (MD) or risk ratios (RR) with the corresponding 95% confidence intervals (CI) in the meta-analysis models using Review Manager (RevMan version 5.4).

Results
Pooling data from 9 RCTs (7300 patients) showed that empagliflozin was superior to placebo in terms of cardiovascular death (RR = 0.57, 95% CI [0.46, 0.71], P &lt; 0.00001), hospitalization due to heart failure (RR = 0.62, 95% CI [0.48, 0.79], P =0.0001), and systolic blood pressure (SBP) (MD = - 8.59, 95% CI [-13.26, -3.93], P = 0.0003). The overall effect did not favor either of the two groups in terms of body weight (MD = - 1.03, 95% CI [-4.05, 1.98], P =0.5), diastolic blood pressure (DBP) (MD = - 1.48, 95% CI [-4.36, 1.41], P =0.3), eGFR (MD = 2.19, 95% CI [-0.10, 4.48], P =0.06), HbA1c (MD = - 0.10, 95% CI [-0.41, 0.22], P =0.5), NT-proBNP (MD = - 115.9, 95% CI [-271.5, 39.6], P =0.1), and adverse events (RR = 0.99, 95% CI [0.97, 1.01], P =0.19).

Conclusions
Ultimately, the current evidence suggests that empagliflozin appears to be an effective treatment option for patients with myocardial infarction who are at high risk for death from cardiovascular causes.Figure 1Figure 2
Effects of SGLT2i on reducing risks of cardiovascular events and dementia in atrial fibrillation patients with diabetes mellitus: a nationwide cohort study
Authors: Chen Y , Chang H C , Chien K L , Hsieh Y C , Chung F P , Lin C H , Lip G Y H , Lin Y L , Chen S A 
Published: November 2023

Abstract

Background/Introduction
Patients with atrial fibrillation (AF) are associated with higher risk for cognitive decline and progression to dementia. There are limited data whether sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces new-onset cognitive dysfunction, especially in Asian patients with AF who also have diabetes mellitus.

Purpose
This study aimed to investigate whether SGLT2i reduces the risks of cardiovascular events and dementia among AF patients with diabetes.

Methods
We identified AF patients with diabetes based on the Taiwan's National Health Insurance Research Database (2016). AF patients without prior dementia history and aged 55-85 years were studied: 810 patients were prescribed SGLT2i for at least 180 days and were matched with 1620 patients without SGLT2i using propensity scores (Figure 1). Cardiovascular and dementia events were followed through the end of 2021. Subtypes of dementia were investigated using competing risk models.

Results
During a follow-up period of 5 years of AF patients with diabetes receiving SGLT2i, as shown in Figure 2, this study provides a detailed insight into the results of survival analyses for clinical outcomes of AF, stroke, total dementia, vascular dementia, all-cause death, and cardiovascular (CV) death. After multivariable adjustment, the risks of AF-related hospitalization (HR: 0.741, 95% CI: 0.563-0.976), stroke (HR: 0.748, 95% CI: 0.599-0.934) and all-cause death (HR: 0.338, 95% CI: 0.245-0.466), were significantly decreased. Both CV death (HR: 0.449, 95% CI: 0.268-0.755) and non-CV death (HR: 0.298, 95% CI: 0.198-0.448) were significantly reduced. SGLT2i use was associated with a significantly decreased risk of total dementia (HR: 0.615, 95% CI: 0.436-0.869) and vascular dementia (HR: 0.419, 95% CI: 0.221-0.793). The reduced risks of Alzheimer’s dementia and other/mixed dementia were not statistically significant. After multivariable adjustment, total dementia and vascular dementia were associated with higher age and stroke events. The beneficial effect on dementia was irrespective of novel oral anticoagulants (NOAC) use, although the SGLT2i benefits were greater in non-warfarin and non-dipeptidyl peptidase 4 (DPP4) users compared to users.

Conclusions
There were decreased risks of AF-related hospitalization, stroke event, all-cause death, and vascular dementia in the users of SGLT2i in AF patients with diabetes. This was irrespective of NOAC use, although the SGLT2i benefits were greater in non-warfarin users compared to warfarin users.Figure 1:Study flow chart
Targeting liver angiotensinogen using a GalNAc-siRNA improves cardiac remodeling in spontaneously hypertensive rats
Authors: Johannes Wikstrom J , Liang J , Cao H , Gao S , Gan L 
Published: November 2023

Abstract

Background
Dysregulation of the Renin-Angiotensin-Aldosterone System (RAAS) leads to hypertension and cardiac hypertrophy. Angiotensinogen (AGT) is the only precursor of all angiotensin peptide products. Liver-specific AGT silencing has been proven to be a promising treatment option in lowering blood pressure (BP) in patients, characterized by full RAAS inhibition and little RAAS escape phenomena. However, the long-term effects of AGT knockdown on cardiac remodeling is still unclear.

Purpose
To explore the long-term effects of a GalNAc-conjugated siRNA drug R0797070 on AGT inhibition, BP and cardiac functions in Spontaneously Hypertensive Rats (SHRs).

Methods
In vitro inhibitory activities of siRNAs were assessed in primary rat hepatocytes. The selected siRNA was conjugated with GalNAc based on RIBO-GALSTAR liver targeting system and named R0797070. In vivo effects of repeated doses of R0797070 were evaluated in SHR model. The animals were treated with R0797070 (3 mg/kg, every 8 weeks; subcutaneous injection) or PBS (5 ml/kg, every 8 weeks; subcutaneous injection) for 7 months with the first dose (day1) at the 3 months of age. Captopril (100 mg/kg per day; oral administration) was taken as a positive drug control and Wistar rats were used as normotensive control group. Blood pressure was monitored by tail-cuff method after an initial acclimatization training period. Serum AGT protein was measured by ELISA and liver mRNA expression was detected by qPCR. Echocardiography was used to determine the changes of cardiac morphology and functions，and wheat germ agglutinin (WGA) staining was used to measure myocyte cross-sectional size.

Results
R0797070 showed 90-99% inhibitory activities on hepatic AGT mRNA at different doses. In SHRs, a single dose of R0797070 at 3 mg/kg resulted in a maximum inhibition of 97% for serum AGT protein with 27 mmHg mean blood pressure (MBP) reduction on Day 15. Daily administration of Captopril could reduce MBP by 33 mmHg on average, while the duration of drug efficacy of R0797070 could reach 2 months with the average 25 mmHg MBP reduction. At the end of study, the echocardiographic results showed that R0797070 significantly reduced left ventricular hypertrophy in the 10-month-old SHRs. Consistently, R0797070 treatment reduced the heart weight by 10%，and LV myocyte size by 17%.

Conclusion
We showed the long-term effects of a GalNAc-siRNA R0797070 on silencing angiotensinogen expression, reducing blood pressure and left ventricular hypertrophy. Compared to daily oral administration of Captopril and its effect on blood pressure R0797070 demonstrated significant effect on cardiac hypertrophy.Figure 1Figure 2
Clinical characteristics and outcomes of super-low-dose edoxaban of 15 mg in patients with acute venous thromboembolism: insight from the COMMAND VTE Registry-2
Authors: Yamashita Y , Chatani R , Kaneda K , Nishimoto Y , Ikeda N , Kobayashi Y , Ikeda S , Kim K , Takase T , Tsuji S , Oi M , Takada T , Otsui K , Sakamoto J , Ogihara Y 
Published: November 2023

Abstract

Background/Introduction
The current guidelines recommend specific durations of anticoagulation therapy depending on the risks of recurrent venous thromboembolism (VTE), and prolonged anticoagulation therapy is recommended for patients at not-low risk of recurrence. However, clinicians are sometimes reluctant to continue anticoagulation therapy for patients with high-bleeding risk. A recent study reported that super-low-dose edoxaban of 15 mg was useful in preventing thromboembolic events for elderly patients with atrial fibrillation who were considered as high-bleeding risk patients. However, super-low-dose edoxaban of 15 mg is currently off-label for VTE all over the world, which could be a potential option for patient with VTE at high-bleeding risk.

Purpose
The current study aimed to investigate clinical characteristics and outcomes of VTE patients with super-low-dose edoxaban of 15 mg, using a large-scale multicenter observational database of patients with VTE.

Methods
The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. After excluding 3193 patients without edoxaban as oral anticoagulation therapy, the current study population was consisted of 2004 patients with edoxaban, who were divided into 3 groups according to initial dosage of edoxaban; 60 mg/day (N=664, 33%) 30 mg/day (N=1309, 65%) and 15 mg/day (N=31, 1.5%).

Results
Patients with edoxaban of 15 mg/day were oldest (60 mg/day: 62.3 years, 30 mg/day: 72.9 years and 15 mg/day: 79.2 years, P&lt;0.001), were most often women (44%, 73% and 84%, P&lt;0.001), showed a lowest mean body weight (68.4, 51.9 and 48.7 kg, P&lt;0.001). Pulmonary embolism as initial presentation was least frequent in patients with edoxaban of 15 mg/day (58%, 44% and 13%, P&lt;0.001). Patients with edoxaban of 15 mg/day most frequently had chronic kidney disease (10%, 22% and 26%, P&lt;0.001) and anemia (45%, 66% and 74%, P&lt;0.001). The discontinuation rates of anticoagulation therapy were not significantly different among the 3 groups (54.4%, 56.5% and 64.8% at 3-year, Log rank P=0.38). The cumulative incidences of recurrent VTE were not significantly different among the 3 groups (6.0%, 6.6% and 0.0% at 3-year, Log rank P=0.31). Similarly, the cumulative incidences of major bleeding were not significantly different among the 3 groups (9.2%, 11.6% and 15.3% at 3-year, Log rank P=0.11).

Conclusions
In the current real-world large VTE registry, a very minority of VTE patients received edoxaban of 15 mg/day, including patients at high-bleeding risk such as old age, low body weight and chronic kidney disease, who did not show significant worse outcomes in terms of recurrent VTE.
Comparisons of effectiveness and safety between different dosage strategy in patients with atrial fibrillation treated with rivaroxaban: a systemic review and meta-analysis
Authors: Chao T , Chan Y H , Lip G Y H , Chen S A 
Published: November 2023

Abstract

Background
Limited real world data show that rivaroxaban following dosage criteria from either ROCKET AF (15mg/day or 10mg/day if creatinine clearance (CrCl)&lt;50ml/min) or J-ROCKET AF (15mg/day or 10mg/day if CrCl&lt;50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We aimed to study whether these observations differ between Asian and non-Asian subjects.

Methods
Databases were searched for adjusted observational study that compared relevant clinical outcomes of NVAF patients receiving off-label under-dosing rivaroxaban (10mg/day if CrCl&gt;50ml/min), on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and off-label over-dosing rivaroxaban (20mg/day if CrCl&lt;50ml/min).

Results
Eighteen studies were included. Rivaroxaban following J-ROCKET AF criteria (n=19,513) was associated with comparable risks of thromboembolism in the Asian subgroup (n=43,076), whereas rivaroxaban following J-ROCKET AF criteria (n=8555) was associated with higher risks of thromboembolism (hazard ratio (HR):1.27;[95% confidential interval (CI):1.05–1.53]) and all-cause mortality (HR:1.30;[95%CI:1.05–1.60]) compared with that of ROCKET AF criteria (n=23,139) in the non-Asian subgroup (n=31,694)(Figure). There was no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian subgroup (Figure). Off-label underdosed rivaroxaban 10mg (n=6305) was associated with a higher risk of thromboembolism (HR:1.64;[95%CI:1.28–2.11]) but lower risk of major bleeding (HR:0.72;[95%CI:0.57–0.90]) compared with eligible dosage criteria (n=11,673). Off-label overdosed rivaroxaban 20mg (n=7572) was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.42;[95%CI:1.14–1.79]), mortality (HR:1.41;[95%CI:1.15–1.73]) and major bleeding (HR:1.27; 95%CI:1.05–1.54; N=7 with I2=25%) compared with eligible dosage criteria (n=39,097).

Conclusions
Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Off-label underdosed rivaroxaban 10mg was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while off-label overdosed rivaroxaban 20mg was associated with worse outcome in most clinical events.
Ischemic and non-ischemic stroke reported in DOAC treated patients with atrial fibrillation and levetiracetam drug interaction: a real-world study
Authors: Abou Kaoud M , Orion D O , Nissan R N , Coster D C , Maor E M 
Published: November 2023

Abstract

Background
To date, the combination of direct oral anti coagulants and some anticonvulsants remain controversial. Therefore, the European Heart Rhythm recommendations do not support using levetiracetam with DOACs.

Objectives
This study sought to investigate reports on ischemic and hemorrhagic stroke with DOACs and the effect of levetiracetam on the rate of reporting in atrial fibrillation patients.

Methods
In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify adverse events associated with DOACs with and without concomitant use of levetiracetam. The authors evaluated disproportionate reporting by the reporting odds ratio adjusted to age and sex (adjROR) and the lower bound of the shrinkage 95% confidence interval (Ω025 &gt; 0 is deemed significant).

Results
The authors identified 1723 (1.3%), 1841 (1.5%), and 3731 (5.3%) MedDRA preferred terms for ischemic stroke in AF patients treated with rivaroxaban, apixaban, and dabigatran, respectively. Whereas reports that described hemorrhagic stroke included, 3016 (2.2%), 1346 (1.1%), and 1256 (1.8%) for rivaroxaban, apixaban and dabigatran. Significant disproportionality signal was identified for ischemic stroke in dabigatran AF patients, (adjROR 3.10; 95%CI, 2.94-3.28). Rivaroxaban demonstrated the lowest adjROR for ischemic stroke when compared to apixaban and dabigatran, (adjROR 0.38; 95%CI, 0.36-0.41). A reciprocal image was noticed for hemorrhagic stroke with a higher reporting odds ratio for rivaroxaban (adjROR 1.46; 95%CI, 1.38-1.55) and a lower reporting odds ratio for dabigatran (adjROR 0.75; 95%CI 0.70-0.78). With regards to the DOAC-levetiracetam-ischemic stroke triplet; rivaroxaban, apixaban and dabigatran illustrated a significant signal in the regression and shrinkage analysis models. The exp(B) 95%CI for the interaction was highest with dabigatran, (exp(B) 3.92; 95%CI, 3.08-3.98).

Conclusions
In this large post-marketing study to date, the authors identified an interaction resulting in decreased effectiveness between levetiracetam and the DOACs. The greatest strength of association was found to be with dabigatran, supporting a P-glycoprotein induction mechanism. The interaction does not seem to influence the risk of hemorrhagic stroke. In line with current studies, ischemic stroke was lowest for rivaroxaban compared to dabigatran and apixaban on account of a higher risk for hemorrhagic stroke. Dabigatran demonstrated significantly lower reporting on hemorrhagic stroke but on account of a higher risk of ischemic stroke. We highly recommend pharmacodynamic monitoring, either anti-Xa for apixaban and rivaroxaban or plasma diluted thrombin time for dabigatran while concomitantly prescribing anticonvulsants with the DOACs.ResultsSensitivity Analysis
Inhibition of Factor XI using a GalNAc-siRNA RBD5049: a novel antithrombotic drug with high potency and long duration
Authors: Gan L , Li C , Sun Y , Wikstrom J , Guo Z , Yu H , Tong C , Zhang H , Liang Z , Gao S 
Published: November 2023

Abstract

Introduction
Bleeding risk remains a major concern of the existing anticoagulants. Inhibition Factor XI (FXI) using small molecule inhibitors, antibodies or antisense oligonucleotides (ASOs) to inactive intrinsic pathway of coagulation have been developed as a safer treatment option over the last decade. siRNA is a nucleic acid drug with class advantages of high selectivity, long duration and benign safety profiles. The current abstract summarizes key preclinical efficacy and safety data supporting the first-in-human study.

Purpose
To evaluate efficacy and safety, of a GalNAc-siRNA molecule RBD4059, for development of a novel antithrombotic treatment.

Methods
In vitro potency of several siRNAs were assessed and screened in HepG2 cells. Upon selection of the lead candidate, the siRNA was conjugated with a GalNAc molecule, using RIBO-GalSTAR liver targeting system. In vivo efficacy of RBD4059 was tested in C57BL/6J mice and cynomolgus non-human primates (NHPs). The antithrombotic effect of RBD4059 was determined in arterial and venous thrombosis models induced by FeCl3. Enoxaparin sodium (Lovenox) with clinical equivalent dose (4 mg/kg) was used as a control. Single- and repeated- dose GLP toxicology studies were performed in both CD-1 mice and NHPs.

Results
IC50 values of RBD4059 was 0.56 nM HepG2 cells. Dose-dependent and long-lasting effects of RBD4059 on the inhibition of plasma FXI activity (FXIa) were observed in mice and in NHPs. RBD4059 at a single dose of 9 mg/kg achieved a maximum of 89% plasma FXIa reduction and 1.38-fold APTT prolongation in mice, and the inhibitory effects could be maintained until Day 64. RBD4059 at 3 mg/kg or 9 mg/kg significantly prevented flow reduction due to FeCl3-induced thrombosis in both arterial and venous thrombosis models, and efficacy was superior than enoxaparin. In NHPs, the inhibitory effects of FXIa were maintained until Day 71 with the maximum effect of 77% FXIa reduction and 1.34-fold APTT prolongation. GLP toxicology studies showed good safety profile without any signs of increased bleeding despite supra-physiological doses and the NOAEL was considered 600 mg/kg in mice and 400 mg/kg in NHPs.

Conclusions
RBD4059 has demonstrated high potency/efficacy and long duration regarding FXI inhibition and with large safety margin. As the first siRNA based molecule targeting FXI, RBD4059 has now entered Phase 1 trial in human healthy volunteers.Figure 1