bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality with bivalirudin plus a high-dose infusion versus heparin in patients with acute coronary syndrome
Authors: Galli M , Gargiulo G , Benenati S , Mehran R , Angiolillo D J 
Published: November 2023

Abstract

Background
The use of bivalirudin in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) has been downgraded by recent international guidelines. The reason for this downgrade lies above all on the excess of acute stent thrombosis (ST) associated with bivalirudin, but subsequent studies have suggested that a post-PCI high-dose bivalirudin infusion may mitigate the risk of acute ST related to the short half-life of bivalirudin.

Methods
We performed an updated meta-analysis of RCTs comparing bivalirudin followed by a post-PCI high-dose infusion versus UFH in ACS. Four RCTs accounting for a total of 16,920 patients were included. Odds ratios (OR) with 95% confidence intervals (CIs) using random effect models were calculated. Number needed to treat (NNT) were also calculated. Clinical outcomes at 30 days were included in the analysis.

Results
Four RCTs accounting for a total of 16,920 patients were included. We found that bivalirudin is associated with a non-significant reduction of 30-day all-cause death (OR 0.81, 95% CI 0.56-1.16, NNT 250, I2 53%), compared with UFH. Results were consistent at a subgroup analysis of STE-ACS versus NSTE-ACS and in a sensitivity analysis excluding the VALIDATE-SWEDEHEART, the only study using a shorter post-PCI bivalirudin infusion (mean 57 min) that was not used in the totality of patients (65%). Moreover, bivalirudin followed by a high-dose infusion was associated with a significant reduction of net adverse clinical events (NACE) (OR 0.62, 95% CI 0.42-0.90, NNT 31, I2 87%) as defined in each trial and of ST (OR 0.47, 95% CI 0.31-0.71, NNT 200, I2 1%), compared with UFH. Finally, BARC 3-5 bleeding was non-significantly reduced (OR 0.36, 95% CI 0.12-1.02, NNT 143, I2 82%) with bivalirudin compared with UFH.

Conclusion
We conclude that bivalirudin followed by a high-dose infusion is associated with reduced ST and NACE compared with UFH, but whether it may reduce all-cause mortality requires further investigations.
Evaluating time in therapeutic range in post-acute myocardial infarction patients with left ventricular thrombus treated with vitamin K antagonist
Authors: Leow A S T , Teo Y N , Teo Y H , Goh F Q , Ho J S Y , Tan B Y Q , Yeo L L L , Li T Y W , Lee E C Y , Wong R C C , Chai P , Yeo T C , Chan M Y Y , Sia C H 
Published: November 2023

Abstract

Background
The standard of care for the treatment of post-acute myocardial infarction (AMI) patients with left ventricular (LV) thrombus is oral anticoagulation with vitamin K antagonist (VKA). Due to the narrow therapeutic range of VKA, patients require frequent monitoring. Adequacy of anticoagulation can be assessed by time in therapeutic range (TTR). This study aimed to evaluate the clinical characteristics and outcomes of post-AMI patients with LV thrombus treated with VKA, stratified by anticoagulation adequacy in terms of TTR ≥70% vs. TTR &lt;70%.

Methods
Among 3000 consecutive echocardiogram results containing the keyword "thrombus" from December 2013 to August 2017, we identified 87 post-AMI patients complicated by LV thrombus and treated with VKA oral anticoagulation. Demographics, treatment including TTR, and outcome measures were analysed.

Results
The cohort was followed up for a median of 4.3 years (IQR 3.6 – 5.3). Patients with and without adequate anticoagulation had no significant differences in terms of age (p = 0.859), gender (p = 0.438), co-morbidities, LV ejection fraction (p = 0.638). A majority of post-AMI patients with LV thrombus treated with VKA had inadequate anticoagulation, as only 25.3% (n = 22) had TTR ≥70%. SAMe-TT2R2 score, a clinical predictor score for adequacy of anticoagulation, was high in the study cohort (median 4, IQR 3 – 5), with no significant difference between the two groups (p = 0.907). On multivariable analysis, TTR &lt;70% was significantly associated with higher incidence of combined outcomes (presence of bleeding, stroke, or mortality) (HR 2.91 [95% CI 1.01 – 8.39], p = 0.048). Patients with TTR &lt;70% had a higher cumulative incidence of bleeding events while on anticoagulation (p = 0.036), and a higher cumulative incidence of overall stroke on Kaplan-Meier analysis, but did not achieve statistical significance (p = 0.077). Patients with TTR &lt;70% had a significantly higher cumulative incidence of combined outcomes (both while on anticoagulation and overall) compared to those with TTR ≥70% (p = 0.026, p = 0.017).

Conclusion
LV thrombus patients treated with inadequate VKA anticoagulation of TTR &lt;70% had overall poorer outcomes compared to TTR ≥70%. Further studies are needed to evaluate anticoagulation adequacy in this population.
The effect of DOAC-Stop on lupus anticoagulant testing in patients with pulmonary embolism receiving direct oral anticoagulants
Authors: Klepczyk A , Zabczyk M , Papuga-Szela E , Undas A , Wypasek E 
Published: November 2023

Abstract

Background
Direct oral anticoagulants (DOACs) are widely used as first-line treatment for pulmonary embolism (PE) but may cause false positive lupus anticoagulant (LA) based on prolongation diluted Russell's viper venom time (dRVVT) or activated partial thromboplastin time (aPTT). Exclusion of antiphospholipid syndrome is recommended in PE patients since this disease requires warfarin, not DOACs.

Aims
We evaluated whether the use of DOAC-Stop, an agent reversing in vitro effects of DOACs, allows for reliable LA testing in PE patients on DOACs.

Methods
We assessed 172 consecutive PE patients aged 48 ± 14 years (50.6 % women) screened for antiphospholipid syndrome according to ISTH guidelines. Blood was collected 1–24 h since intake of a DOAC, i.e. rivaroxaban (n=81, 47.1%), dabigatran (n=53, 30.8%) and apixaban (n=38, 22.1%). LA testing was performed after DOAC-Stop (Haematex Research, Hornsby, Australia) treatment. Positive LA was reported when the normalized (patient/standard plasma clotting time) LA screening and screening (LA1)/confirmation (LA2) ratios exceeded 1.2.

Results
In screening tests after DOAC-Stop use, the dRVVT remained prolonged in 9 (5.2%) patients including 4 (44.5%) on apixaban, 3 (33.3%) on rivaroxaban and 2 (22.2%) on dabigatran, while the dRVVT LA1/LA2 ratio was abnormal in 7 (4.1%) subjects: 3 (42.9%) were on apixaban, 3 (42.9%) on rivaroxaban and 1 (14.2%) on dabigatran. In 2 (22,2%) patients the dRVVT LA1/LA2 ratio exceeded 2. The aPTT-LA screening test remained prolonged in 8 (4.6%) patients including 4 (50.0%) on apixaban, 2 (25.0%) on rivaroxaban and 2 (25.0%) on dabigatran, while the aPTT LA1A/LA2A ratio was abnormal in 5 (2.9%) patients: 3 (60.0%) on apixaban, 1 (20.0%) on rivaroxaban and 1 (20.0%) on dabigatran). In 1 (12.5%) patients the aPTT LA1/LA2 ratio exceeded 2.
Antiphospholipid syndrome with the presence of LA was diagnosed in 7 (87.5%) patients. False positive LA had 1 (0.6%) patients after the DOAC-Stop use.

Conclusion(s)
To our knowledge, this is the largest cohort of PE patients on DOACs evaluated for LA, with use of DOAC-Stop, showing reliability of such approach in the real-life setting, with &lt;1% of patients with false positive LA.
Pattern of dual antiplatelet use and 12-month outcomes stratified by bleeding and ischemic risk in acute coronary syndrome patients undergoing percutaneous coronary intervention
Authors: Yan B , Lai A , Sun H , Tam T K , Tan G M 
Published: November 2023

Abstract

Background
There is a need to understand real-world antiplatelet usage in different risk group patients to provide insights into personalised approach to acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI).

Purpose
We aimed to evaluate patterns and outcomes of antiplatelet therapy use in ACS patients undergoing PCI according to their bleeding and ischemic risks.

Methods
We retrospectively analysed 3,577 consecutive ACS patients who underwent urgent or emergent PCI from 16 hospitals in between Jan 2016 to Dec 2020. Patients were stratified according to their (i) bleeding risk using PRECISE-DAPT score ≥25 as high (HBR) and &lt;25 as low bleeding risk (LBR) and further by (ii) ischemic risk if any one of the following: diffuse multi-vessel disease, chronic kidney disease, ≥3 stents implanted or lesions treated, total stented length &gt;60mm, chronic total occlusion and history of STEMI is present as high ischemic risk (HIR) or absent as low ischemic risk (LIR). Pattern of dual-antiplatelet (aspirin plus clopidogrel or ticagrelor) use and 12-month outcomes including major bleeding, recurrent MI and cardiovascular (CV) death were compared between HBR, LBR, HIR and LIR groups. Independent predictors of antiplatelet therapy use and clinical events were identified using multi-variate analysis.

Results
Of 3,577 patients, 25.6% (n=914) are HBR and 74.4% (n=2663) LBR. 86.5% (793/914) of HBR patients also had HIR. Overall usage of aspirin plus clopidogrel was 48.4% and ticagrelor 48.3%. Usage of ticagrelor was significantly higher in LBR (54.0%) compared to HBR (31.8%) patients (p&lt;0.01) but not significantly different between HIR (30.4%) and LIR (41.3%) patients (p=NS). HBR was an independent predictor against ticagrelor use with odds ratio of 0.48 (95% confidence interval 0.38 to 0.60). Aspirin plus ticagrelor compared to aspirin plus clopidogrel was associated with significantly lower recurrent MI rates in both HBR (9.3% vs. 22.7%) and LBR (3.0% vs. 6.0%, both p&lt;0.01) patients, higher bleeding risk in HBR (1.7% vs. 0.5%, p&lt;0.01) but not in LBR (0.6% vs 0.9%, p=NS) and no significant differences in CV death rates in both HBR (3.4% vs. 5.3%) and LBR (1.0% vs. 0.9%, both p=NS) at 12-months.

Conclusions
In our cohort of ACS patients undergoing PCI, a quarter have HBR of which majority also have HIR. Patients’ bleeding risk was a stronger determinant of dual-antiplatelet therapy choice than ischemic risk. Aspirin and ticagrelor was associated with significantly lower recurrent MI rates irrespective of bleeding risk but high major bleeding rates in HBR but not LBR patients. Our results support personalised approach to dual-antiplatelet therapy use based on bleeding risk.
Are heart failure patients with mildly reduced ejection fraction treated according to current international guidelines?
Authors: Schupp T , Pumpe K P , Abel N A , Reinhardt M R , Schmitt A S , Weidner K W , Akin I A , Behnes M B 
Published: November 2023

Abstract

Objective
This study aims to investigate the guideline adherence and prognostic role of guideline recommended heart failure (HF) therapies in patients hospitalized with heart failure with mildly reduced ejection fraction (HFmrEF).

Background
Limited data regarding the guideline adherence and prognostic impact of different pharmacotherapies in patients with HFmrEF is available.

Methods
A large retrospective study was used including all consecutive hospitalized patients with HFmrEF (i.e., left ventricular ejection fraction (LVEF) 41 – 49%) from 2016 to 2022 according to current European guidelines. The prescription rates and the prognostic role of angiotensin-converting enzyme and receptor blockers (ACEi/ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium glucose linked transporter 2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitor"(ARNi) was assessed. The primary endpoint was the first heart-failure related re-hospitalization at 3 years. Secondary endpoints comprised amongst others cardiovascular re-hospitalization. Kaplan-Meier, uni- and multivariable Cox regression analyses were applied for statistics.

Results
775 consecutive patients with HFmrEF surviving index hospitalization were included. Of those, 73% were discharged on ACEi/ARB, followed by BB (26%), 14% MRA, whereas only minor part was treated with SGLT2i (3%). In HFmrEF patients, no prognostic impact of BB (10% vs. 7%; log rank p=0.218; HR=1.474; 95% CI 0.792-2.742; p=0.220), ACEi/ARB (9% vs. 10%; log rank p=0.444; HR=0.822; 95% CI 0.497-1.359; p=0.445), SGLT2i (8% vs. 9%; log rank p=0.821; HR=0.851; 95% CI 0.209-3.470; p=0.445), MRA (8% vs. 9%; log rank p=0.748; HR=0.892; 95% CI 0.443-1.794; p=0.748) regarding the risk of heart-failure related re-hospitalization at 3 years was observed. In line, these pharmacotherapies were not associated with the risk of cardiovascular re-hospitalization.

Conclusions
In patients hospitalized with HFmrEF between 2016 and 2022, only infrequent treatment with guideline recommended HF therapies was observed, whereas non of the current HF therapies was associated with the risk of heart-failure related rehospitalization.
The clinical implementation of a de-escalation strategy using CYP2C19 genotyping in patients with an acute coronary syndrome: insights from the FORCE-ACS registry
Authors: Azzahhafi J , Van Den Broek W W A , Chan Pin Yin D R P P , Ten Berg J M 
Published: November 2023

Abstract

Background
Current guidelines recommend prasugrel and ticagrelor in patients undergoing percutaneous coronary intervention (PCI), however these potent P2Y12-inhibitors are associated with a higher bleeding risk when compared to clopidogrel. The CYP2C19 gene influences the efficacy of clopidogrel, with carriers of loss-of-function alleles having a higher risk for major adverse cardiovascular events. A genotype-guided strategy whereby noncarriers are treated with clopidogrel has been shown to reduce bleeding without increasing the risk of major adverse cardiovascular events and to be cost-effective. Currently, there are no practical guidelines for implementing a genotype-guided strategy and there are still operational issues regarding the usage of buccal swabs or venous blood samples.

Purpose
The study aimed to assess the feasibility of a CYP2C19 genotype-guided de-escalation strategy in acute coronary syndrome (ACS) patients treated with dual antiplatelet therapy and to evaluate the de-escalation rate.

Methods
ACS patients receiving genotype-guided antiplatelet therapy from August 2021 onwards were eligible. Genotyping was done using buccal swabs in a point-of-care (POC) device or by venous blood samples in the lab. Genotyping results were entered into the EHR. Attending physicians received automatic notifications to change antiplatelet therapy based on genotyping results, but subsequent management was at their discretion. The primary endpoint is maintenance therapy with P2Y12 inhibitors, with secondary endpoints being therapy changes, and time until genotype results. Therapy changes based on genotyping method were assessed using the Chi-square and Mann-Witney U test.

Results
In total, 1,530 patients with suspected ACS were included in the FORCE-ACS registry from June 2021 to January 2023. A CYP2C19 genotype test was performed in 738 ticagrelor treated patients and 260 (35%) patients carried a CYP2C19 LoF-allele. The median time to genetic test result was 6.2 hours, with 84.6% of results known within 24 hours for POCT and 15.4% for blood analysis. Of all 478 CYP2C19 LoF-allele noncarriers eligible for de-escalation, 433 (90.4%) patients were successfully de-escalated from ticagrelor to clopidogrel. De-escalation to clopidogrel occurred within 24 hours in 70.9% of patients and within 48 hours in 93.1%. The time to de-escalation was significantly lower in patients analyzed using POCT (25.4 hours) compared to blood analysis (58.9 hours).

Conclusion
The implementation of routine genotyping is feasible and de-escalation rates to clopidogrel in non-carriers are acceptable. The quicker time-to-results and de-escalation highlights the potential benefits of using POC testing.Overview of genotype-guided strategy
The inflammatory proteome and risk of atrial fibrillation: genetic insights into causal relevance
Authors: Camm C J F , Casadei B , Hopewell J C 
Published: November 2023

Abstract

Background
Cardiac and systemic inflammation have been associated with a higher risk of atrial fibrillation (AF) in both animal models and human studies. Causality, however, has been questioned due to inconsistent efficacy of anti-inflammatory treatments in preventing incident or recurrent AF, and potentially confounding associations with AF risk factors such as ischaemic heart disease. Inflammatory processes are highly complex and involve a large number of proteins, but the individual relevance and causal role of these for AF remains unclear.

Purpose
To explore the nature of the relationship between the inflammatory proteome and risk of AF.

Methods
Associations between 26 inflammatory proteins and AF were assessed in a two-sample Mendelian randomization (MR) framework, with primary MR causal estimates with AF estimated among 339,214 White British UK Biobank (UKB) participants (AF cases=30,630). MR analyses for each inflammatory protein included independent variants previously associated with the relevant protein at genome-wide significance (p&lt;5x10-8) across the genome (trans-protein quantitative trait loci [pQTLs]), or restricted to at least 50kb from the closest upstream gene and 50 kb downstream from the target gene (cis-pQTLs). Sensitivity analyses to assess potential pleiotropy were conducted (MR-Egger, weighted median, and weighted mode). Associations passing multiple testing threshold (p&lt;0.002) in UKB were further validated in meta-analyses with independent datasets including over 50,000 AF cases (FinnGen and AFGen). Research undertaken using UKB application 14568.

Results
This inflammatory protein-wide study identified three proteins that have support for causal associations with AF. Genetically-predicted levels of IL6R, CD40, and Chitinase-3-like protein 1 (YKL40) each showed a negative association with risk of AF, with up to a 5% lower AF risk per standard deviation higher genetically-predicted levels of these proteins (Figure 1). These findings were further confirmed in meta-analysis with data from AFGen and FinnGen. No evidence of pleiotropy was identified, and results were also confirmed in cis-pQTL analyses, which were fully consistent with the trans-pQTL analyses (Table 1). Analyses stratified by various baseline characteristics highlighted stronger causal estimates in those with higher levels of C-reactive protein (with interaction p-values &lt;0.001).

Conclusions
Genetic approaches support the relevance of lifelong differences in the inflammatory proteome for AF, and causal relationships between specific inflammatory markers and risk of AF. Greater soluble IL6R and CD40 as measured in proteomic analyses are both associated with lower levels of inflammation. As previous work indicates that genetically upregulated CD40 and IL6R are similarly associated with a lower risk of ischemic stroke, the risk-benefit of directly targeting these pathways needs further consideration.Figure 1Table 1
CYP2C19 genotype prevalence and association with recurrent myocardial infarction in British-South Asians treated with clopidogrel
Authors: Magavern E F , Jacobs B , Warren H , Finocchiaro G , Finer S , Van Heel D A , Smedley D , Caulfield M J 
Published: November 2023

Abstract

Background
Pharmacogenomics examines how genes and drugs interact to explain some of the inter-individual variability in response to medications. CYP2C19 is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Although the European Society of Cardiology and National Institute for Care Excellence recommend ticagrelor (a non CYP2C19 dependent P2Y12 antagonist) as the antiplatelet agent of choice, clopidogrel remains widely prescribed for acute coronary syndrome and myocardial infarction. CYP2C19 poor metabolizers are known to be more common in Asian ancestry but very few studies have looked specifically at South Asian populations or linked metabolizer diplotypes with clinical efficacy data in this population. The outcome studies on which clopidogrel was licensed for efficacy and safety did not include significant South Asian representation. Furthermore, South Asians are known to have a higher prevalence of cardio-metabolic disease compared with European ancestry populations.

Methods
We studied the Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants to look at prevalence of CYP2C19 metabolizer genotypes and correlate these with recurrent myocardial infarction risk for those who had been prescribed clopidogrel in primary care. Multivariable regression was used to test for association between known CYP2C19 diptotypes and recurrent myocardial infarction in those prescribed clopidogrel, controlling for known CVD risk factors, percutaneous coronary intervention, age, and gender.

Results
Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss of function allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss of function alleles is 13%, which is higher than in previously studied European (2.4%) and Central/South Asian populations (8.2%). This is primarily due to the *2 LOF allele present in 56% of the population. 69% of the cohort who were diagnosed with an acute MI were prescribed clopidogrel. The presence of the poor metabolizer diplotype is significantly associated with higher risk of recurrent MI, or failed secondary prevention on clopidogrel in this population, OR 3.1 (p = 0.02), with some subsequent ischemic events already described in this young cohort (Acute MI prescribed clopidogrel N = 697, Recurrent MI in this group N=39).

Conclusions
A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry. In absence of genotype guided prescribing, maximal adherence to guidelines recommending non CYP2C19 dependent P2Y12 anti-platelet therapy is likely to be disproportionately beneficial in this ethnic cohort.Risk of recurrent MICentral illustration