bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomarkers for detection of anthracycline-induced cardiomyopathy in childhood cancer survivors: a case-control study in the Dutch LATER cohort study
Authors: Leerink J.M , Feijen E.A.M , Mavinkurve-Groothuis A.M.C , Tissing W.J.E , Louwerens M , Van Den Heuvel-Eibrink M.M , Versluys A.B , Van Dulmen-Den Broeder E , De Vries A.C.H , Van Der Pal H.J.H , Kapusta L , Loonen J , Pinto Y.M , Kremer L.C.M , Kok W.E.M 
Published: November 2020

Abstract

Introduction
Plasma biomarkers may aid in the surveillance for anthracycline-induced cardiomyopathy (ACM) in long-term childhood cancer survivors and provide insight into the pathophysiological mechanisms involved. In this pilot study, we aimed to identify new plasma markers associated with ACM.

Methods
A case-control study within the Dutch Late Effects After Childhood Cancer Cohort study (Dutch LATER) was conducted. We compared 184 plasma markers (Olink) between ACM cases (LVEF&lt;45%) and anthracycline treated controls (LVEF≥53%), matched on sex, time since cancer diagnosis and anthracycline dose. Associations of plasma markers with ACM were assessed with conditional logistic regression. Pathway analysis was performed with STRING (string-db.org). Significant markers were evaluated in multivariable models next to anthracyclines dose, sex and time after cancer.

Results
In total, 28 ACM cases (median anthracycline dose 351 mg/m2; median age at study 38 years, 29% chest radiotherapy) and 29 controls (median anthracycline dose 300 mg/m2; median age at study 44 years, 7% chest radiotherapy) were included. Eight markers were significantly associated with ACM (Table 1) and were implicated in ventricular wall stress, apoptosis, inflammation and endothelial dysfunction (Figure 1). The AUC of the model including only the clinical variables was 0.73 (95% confidence interval (CI) 0.60–0.86), and improved to 0.82 (95% CI 0.71–0.94) with the addition of NT-proBNP and further to 0.86 (95% CI 0.76–0.97) with the addition of all 8 markers.

Conclusion
In this biomarker discovery study, 8 markers related to ventricular wall stress, apoptosis, inflammation and endothelial dysfunction were associated with ACM. We intend to validate these markers quantitatively in the Dutch LATER cohort study.
Figure 1. Pathway analysis of significant markers

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation Grant; Amsterdam University Funding
Differential effect of anthracycline and trastuzumab cancer therapeutic related vascular toxicity in patients with breast cancer
Authors: Anastasiou M , Oikonomou E , Vogiatzi G , Siasos G , Flora Z , Antonopoulos A.S , Tsalamandris S , Bamias A , Dimopoulos M.A , Tousoulis D 
Published: November 2020

Abstract

Introduction
Both anthracyclines and trastuzumab are key regiments for the treatment of breast cancer, but their concurrent use is contraindicated because of their cardiotoxicity. Their effects on vascular function have been less well studied.

Purpose
We explored the effects of the anthracycline-based chemotherapy followed by trastuzumab-based treatment on endothelial function and arterial stiffness in patients with breast cancer.

Methods
46 female patients (54.56±11.5 years old) with breast cancer scheduled for anthracycline-based chemotherapy followed by the combination of trastuzumab and taxane were enrolled. Trastuzumab was continued until the completion of one-year treatment. All participants underwent assessment of the brachial flow mediated dilatation (FMD), endothelial independent dilatation (EID), carotid-femoral pulse wave velocity (PWV) and augmentation index (AIx) at baseline (BL), at the end of anthracycline treatment (FU1), 3 months following initiation of trastuzumab with taxane (FU2) and at the completion of treatment with trastuzumab (FU3).

Results
Over the follow-up period (15 months) there was significant deterioration in FMD (p=0.04) (Table 1, Figure 1). Importantly, while there was no significant difference in FMD between BL vs FU1 (p=0.6), FMD has been significantly deteriorated over the treatment with trastuzumab with taxane FU1 vs FU2 (p=0.01) and FU2 vs FU3 (p=0.01) (Table 1, Figure 1). EID did not change over the follow-up period (Figure 1). Similarly, PWV has been significantly increased over the follow up period (p=0.03). There was no significant difference in PWV BL vs FU1 (p=0.1), however PWV has been significantly increased over the treatment with trastuzumab with taxane FU1 vs FU 2 (p=0.02) and FU2 vs FU3 (p=0.01) (Table 1, Figure 1). A similar pattern of impairment was observed with AIx (Table 1, Figure 1).

Conclusion
We report a significant adverse effect of the anthracycline- and trastuzumab-based therapy on the arterial stiffness and endothelial function. This effect is more considerable after the exposure to trastuzumab.
Figure 1. Changes of FMD, PWV, Alx, EID during FU

Funding Acknowledgement
Type of funding source: None
Characterisation of patients with concomitant cancer in significant aortic stenosis
Authors: Sia C , Ngiam N , Chew N , Loi J.W.B , Tan B.Y.Q , Sim H.W , Kong W.K.F , Tay E.L.W , Yeo T.C , Poh K.K 
Published: November 2020

Abstract

Background
There is an increasing incidence of cancer worldwide, while aortic stenosis is the most common valvular heart disease. However, management of aortic stenosis (AS) in patients with cancer remains poorly understood. The presence of concomitant AS in patients with cancer may confer added morbidity and mortality.

Methods
We studied 727 consecutive patients with index echocardiographic diagnosis of moderate to severe aortic stenosis (aortic valve area &lt;1.5cm2). These patients were divided in patients with or without concomitant cancer. Baseline clinical and echocardiographic parameters were compared by appropriate univariate analyses. Kaplan-Meier curves were constructed to compare mortality, admissions for congestive cardiac failure and aortic valve replacement between the groups.

Results
Eighty-five (11.7%) patients had concomitant cancer with moderate to severe AS. Of those, 45 (52.9%) had active cancer. The group with cancer was similar in terms of age, body mass index, clinical comorbidities compared to the group without cancer. AS severity and echocardiographic profile was similar except for a lower LVIDd (43.6±12.0 vs 47.4±8.9mm, p&lt;0.001), and LV mass index (103.1±43.2 vs 116.6±41.5, p=0.005). There was higher mortality in the cancer group (log-rank 17.6, p&lt;0.001), similar incidence of admissions for cardiac failure (log-rank 0.58, p=0.446) and a lower incidence of aortic valve replacement (log-rank 3.96, p=0.047) compared to the group without cancer. Patients with AS who received cancer treatment did better than those that did not receive cancer treatment.

Conclusion
Concomitant cancer in patients with moderate to severe AS was associated with increased mortality, and a lower incidence of aortic valve replacement. Further studies are warranted to investigate the role of valve replacement in patients with cancer.
Figure 1

Funding Acknowledgement
Type of funding source: None
Lifetime risk of cardiovascular-renal disease in type 2 diabetes: a population-based study in 473399 individuals
Authors: Zhang R , Mamza J , Morris T , Godfrey G , Asselbergs F , Denaxas S , Hemingway H , Banerjee A 
Published: November 2020

Abstract

Background
Lifetime risks of cardiovascular (CV) and renal diseases are high, particularly in type 2 diabetes (T2D), but rarely studied together, and relative disease contributions are unknown. Knowledge of lifetime risk of cardiovascular-renal disease (CVRD) will better reflect disease burden in T2D.

Purpose
To investigate the lifetime risks (LTRs) of composite and individual components of major adverse reno-cardiovascular events, MARCE in T2D patients.

Method
In a population-based cohort study using national electronic health records, we studied 473399 individuals aged 45–99 years with T2D in England 2007–2018. The LTR of composite and individual components of MARCE (including CV death and CVRD: heart failure, HF; chronic kidney disease stage 3 and above, CKD; myocardial infarction, MI; stroke or peripheral artery disease, PAD) were estimated. LTRs by baseline CVRD comorbidity status were compared with individuals free from CVRD at baseline, accounting for the competing risk of death.

Results
Among T2D patients aged ≥45 years, the LTR of MARCE was 80% for individuals free from CVRD at baseline. LTR of MARCE was 97%, 93%, 98%, 89% and 91% for individuals with specific CVRD comorbidities for HF, CKD, MI, stroke and PAD, respectively at baseline. Within the CVRD-free cohort, LTR of CKD was highest at 54%, followed by CV death (41%), HF (29%), stroke (20%), MI (19%) and PAD (9%). Compared to CVRD-free, HF, MI and CKD at baseline were associated with the highest LTR of MARCE and its component diseases (Table).

Conclusion
The lifetime risk of CV disease and CKD in T2D patients is estimated to be over 60% and 50% respectively (1–3). When considered together, the LTR of MARCE is 80% in CVRD-free T2D patients, while nearly all those with T2D and HF will develop MARCE over their lifetime. Of the individual components of MARCE, LTR of CKD and HF were the highest among CVRD-free T2D patients. Preventive measures in T2D patients should be a priority in clinical practice to mitigate the burden of these complications.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): AstraZeneca
High dialysis clearance of drugs predicts intradialytic hypertension in hemodialysis patients
Authors: Tokareva A , Borovkova N , Polyakova I 
Published: November 2020

Abstract

Introduction/Purpose
An acute drop in highly dialyzable antihypertensive drug levels is considered to be one of the pathophysiological mechanisms of blood pressure rise during hemodialysis (HD). The study aimed to assess the prevalence of intradialytic hypertension (ID-HTN) and identify the most significant risk factors of its development.

Methods
We performed a retrospective case-control single-center study of HD patients from January 1st, 2014 to December 30th, 2016. Baseline evaluation included recording of antihypertensive medications with a focus on dialyzability of drugs. ID-HTN was defined as an increase in systolic blood pressure more than 10 mmHg after HD session.

Results
We enrolled 131 HD patients (52% males, median age 55.7 [53.5; 58.0] years, dialysis vintage 59.3 [51.8; 66.8] months). 79 patients suffered from ID-HTN. Highly dialyzable drugs were used in 61% of patients, most often – in 68% of cases – in the group of beta-blockers, less often among inhibitors of angiotensin-converting enzyme (32%).
ID-HTN was associated with use of beta-blockers (Spearman's rank correlation coefficient (r)=0.212; p=0.015), moxonidine (r=0.313; p=0.001) and highly dialyzable drugs (r=0.440; p&lt;0.0001). Using the identified risk factors, a prediction model for ID-HTN based on logistic regression was constructed: y = −1.015 + 1.720 × highly dialyzed drugs + 0.993 × moxonidine; p = exp (y) / (1 + exp (y)).
Table 1 displays actual and predicted values on the sample of HD patients.

Conclusion
In present study 60% of dialysis patients suffered from ID-HTN. Drugs with high dialysis clearance were widely used (61%) in dialysis population. Highly dialyzable drugs were associated with increased risk of ID-HTN (OR 5.585; 95% CI 2.49–12.54; p&lt;0.0001). The low specificity (65.4%) of the prediction model limits its use in clinical practice.
Figure 1 shows the covariate-adjusted ROC curve by logistic regression model.

Funding Acknowledgement
Type of funding source: None
Vericiguat clinical pharmacology programme: biopharmaceutical properties and potential intrinsic and extrinsic factor effects
Authors: Boettcher M , Aliprantis A.O , Lobmeyer M , Meyer M , Mueck W , Trujillo M , Becker C 
Published: November 2020

Abstract

Introduction
The Phase III VICTORIA study (NCT02861534), which evaluated vericiguat vs placebo in patients with worsening chronic heart failure (WCHF) with ejection fraction &lt;45%, demonstrated a significant reduction in the primary composite endpoint of cardiovascular death and HF hospitalisation.

Purpose
A comprehensive clinical pharmacological programme of 28 Phase I trials in &gt;650 participants was performed to inform use of vericiguat.

Methods
Biopharmaceutical properties, pharmacokinetics (PK) and the potential for intrinsic factors to influence vericiguat dose administration were investigated. The PK and pharmacodynamic (PD) interaction potential of vericiguat with other drugs was assessed.

Results
Vericiguat had a mean half-life of approximately 24 h and high bioavailability when taken with food, leading to the recommendation of once daily dosing with food. Due to the multi-pathway metabolism and excretion profile of vericiguat, there was a low risk of PK drug–drug interactions (DDI; Table). No clinically relevant PD DDI were identified between vericiguat and aspirin, warfarin, sacubitril/valsartan or nitrates. There was a relatively minor influence of intrinsic factors on vericiguat PK.

Conclusion
This clinical pharmacology programme supports use of vericiguat in patients with WCHF who are characterised by multiple comorbidities and polypharmacy.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Funding for this research was provided by Bayer AG, Berlin, Germany and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Analysis of first plus recurrent cardiovascular (CV) and hospitalisation events in the CAROLINA trial
Authors: Marx N , McGuire D.K , Johansen O.E , Rosenstock J , Pfarr E , Mattheus M , George J.T , Espeland M.A , Zinman B 
Published: November 2020

Abstract

Background/Introduction
CAROLINA (cardiovascular outcome study of linagliptin versus glimepiride in type 2 diabetes) was a randomised controlled clinical trial designed to compare the effects of linagliptin with glimepiride on CV events and other outcomes in patients with relatively early type 2 diabetes at elevated CV risk.

Purpose
To characterise the effects on net CV disease and the hospitalisation burden of this population, we assessed the effects of linagliptin vs glimepiride on all first plus recurrent CV events and all cause hospitalisations.

Methods
Participants with relatively early type 2 diabetes, high CV risk and HbA1c 6.5–8.5% were randomized to linagliptin 5 mg or glimepiride 1–4 mg once daily on top of standard of care. Cox regression was used to produce hazard ratios for time to first event. A negative binomial model was used to produce event rate ratios for all events.

Results
A total of 6033 participants were enrolled (mean age 64.0 years, HbA1c 7.2%, body mass index 30.1 kg/m2, eGFR 77 ml/min/1.73 m2, median type 2 diabetes duration 6.3 years, urine albumin:creatine ratio 10 mg/g, 42% with CV disease, 4.5% with heart failure). Adding recurrent events increased the number of events for analysis from first event by 10% more to 77% across CV/heart failure outcomes and by 119% for all cause hospitalisations, with corresponding increases in rates per 100-patient years in both treatment groups (e.g. for the composite of CV death/MI/stroke from 2.1 to 2.8 for linagliptin and 2.1 to 2.9 for glimepiride) over a median follow up of 6.3 years. Results of analyses of first-event and first plus recurrent events are presented below (Fig).

Conclusion
No significant differences were observed between linagliptin and glimepiride for either first or first + recurrent CV or hospitalisation events. These data underscore the significant CV disease burden experienced even in relatively early type 2 diabetes and reinforce the similar CV safety between linagliptin and glimepiride, differing only on hypoglycaemia risk.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company
Clinical outcome with NOACs vs VKAs in patients with atrial fibrillation and severe chronic kidney disease: results of a retrospective, multicenter, real-world study
Authors: Lio V , Pasceri V , Di Lullo L , Russo V , Fimiani F , Calabro' P , Petroni R , Grimaldi M , Renda G , Pignatelli P , Romano S , Penco M , Patti G 
Published: November 2020

Abstract

Background
Patients with atrial fibrillation (AF) and severe chronic kidney disease (CKD) are at higher risk of both bleeding and thromboembolic events. Non-vitamin K antagonist oral anticoagulants (NOACs) are licensed to be used in these patients, although they were excluded from phase III controlled randomized trials comparing NOACs vs warfarin in AF. Thus, current evidence on NOACs use in such setting of patients is not definitive.

Purpose
Aim of our multicenter study was to perform a real-world comparison of clinical outcome with NOACs vs vitamin K antagonist anticoagulants (VKAs) also in AF patients having an estimated glomerular filtration rate (eGFR) 15–29 mL/min.

Methods
We retrospectively included a total of 266 patients receiving NOACs (N=159) or VKAs (N=107). Primary outcome measure was the cumulative incidence of the net composite endpoint including ischemic stroke, systemic thromboembolism or any bleeding. Mean follow-up was 2.6 years.

Results
CHA2DS2-VASc and HAS-BLED scores at baseline were similar in the two groups (3.4±1.3 with NOACs vs 3.4±0.9 with VKAs and 3.1±1.0 vs 3.0±0.7, respectively); eGFR and hemoglobin values were also comparable (31.8±12.3 vs 32±11.9 mL/min and 10.2±2.1 vs 11.0±2.3 g/dL, respectively). NOACs were not inferior to VKAs for the primary net composite endpoint: incidence 20.7% vs 29.9%, p&lt;0.01 for non-inferiority, p=0.11 for superiority. In proportional Cox regression model, hazard ratio for the primary outcome measure with NOACs use was 0.74 (95% CI 0.45–1.21, p=0.22). In the NOAC group there was a trend towards reduction in minor bleeding complications (p=0.08).

Conclusions
Our real-world data indicate that in patients with AF and severe renal failure NOACs are not inferior to VKAs for both safety and efficacy. The use of NOACs was associated with a numerically lower incidence of minor bleeding.

Funding Acknowledgement
Type of funding source: None
Pharmacokinetics of apixaban in patients with end stage renal disease on hemodialysis and atrial fibrillation: results from the RENAL-AF trial
Authors: Pokorney S , Garonzik S , Chertow G.M , Washam J.B , Mussina K , Bansal N , Gadegbeku C , Garcia D , Lopes R.D , Mahaffey K.W , Middleton J , Thadhani R , Thomas K.L , Winkelmayer W , Granger C.B 
Published: November 2020

Abstract

Background/Introduction
Apixaban use is increasing for stroke prevention in patients with atrial fibrillation (AF) and end stage renal disease (ESRD) on hemodialysis. There is uncertainty as to the optimal dose in this population in part related to the limited available pharmacokinetic (PK) data.

Purpose
We comprehensively evaluated the PK of apixaban collected over 1 month of apixaban dosing in 63 patients with AF and ESRD on hemodialysis.

Methods
Patients with AF and ESRD on hemodialysis were randomized to warfarin versus apixaban within the RENAL-AF trial with 5 mg BID dosing, except for 2.5 mg BID in those age ≥80 years or weight ≤60 kg. The 5 mg BID dose could be reduced to 2.5mg BID for minor bleeding. Day 1 PK data was collected on all patients pre- and post-hemodialysis. Day 3 and 1 month pre- and post-hemodialysis PK samples were collected in 49 patients. The timing of apixaban dosing and hemodialysis relative to PK samples was recorded. Dosing history, hemodialysis, and PK samples were chronologically integrated with patient specific data such as body size, age, race and gender. This dataset was combined with the ARISTOTLE dataset, and the published PK model from ARISTOTLE describing exposures in the AF population was updated to incorporate an additional clearance term for hemodialysis. The model estimated apixaban exposures (AUC) in RENAL-AF were compared to ARISTOLTE AUC values.

Results
There were 285 PK concentrations collected among 63 patients in the RENAL-AF trial. Patients had median age 69 years with 41% women (N=26) and a median weight of 84 kg (49, 157). The median AUCs for patients with ESRD on hemodialysis were 5,452 and 2,990 for patients treated with 5mg BID and 2.5mg BID doses, respectively. The median AUCs for patients treated with 5mg BID from ARISTOTLE increased from 2,802 for patients with class 1 CKD to 5,863 for class 4 CKD, while they increased from 2,392 for class 1 CKD to 2,881 for class 4 CKD in patients treated with 2.5mg BID. The median AUC for patients with ESRD on hemodialysis were within 50% of the exposure of patients from ARISTOTLE for all classes of CKD for the 2.5mg BID dose and for classes 2, 3A, 3B, and 4 CKD for the 5mg BID dose (Figure).

Conclusions
The steady state apixaban exposure data in patients with AF and ESRD on hemodialysis were modestly higher but consistent with the results of non-ESRD patients from ARISTOTLE, using 5 mg BID unless patients had age ≥80 years or weight ≤60 kg. Additional clinical outcomes data on the use of apixaban in patients with AF and ESRD on hemodialysis are needed.

Funding Acknowledgement
Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Investigator sponsored grant from Bristol-Myers Squibb and Pfizer
The impact of discontinuation of aspirin within 24 months among the high risk patients who are receiving prolonged dual antiplatelet therapy after implantation of second-generation drug-eluting stents
Authors: Cho S.W , Kim D.Y , Park T.K , Lee J.M , Yang J.H , Song Y.B , Choi J.H , Choi S.H , Gwon H.C , Lee S.H , Hahn J.Y 
Published: November 2020

Abstract

Background
The clinical impact of discontinuation of aspirin within 24 months after PCI for high risk patients who are receiving prolonged dual antiplatelet therapy (DAPT) is not known. We investigated the long-term outcomes prolonged DAPT among high risk patients after second-generation drug-eluting stent (DES) implantation.

Methods and results
Of 2082 consecutive patients undergoing PCI using 2nd generation DES, we studied 637 patients at high risk either angiographically or clinically who received clopidogrel longer than 24 months and were event-free at 12 months after index PCI. Patients were divided into 2 groups: the clopidogrel monotherapy group (aspirin discontinued within 24 months) and the prolonged DAPT group. The primary outcome was major adverse cardiac and cerebrovascular events (a composite of all-cause death, non-fatal myocardial infarction, or stroke) between 12 and 36 months after the index procedure.
In propensity score-matched population, the risk of major adverse cardiac and cerebrovascular events (4.7%, 12/256 versus 4.3%, 11/256, hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.42–2.16, p=0.91), all-cause mortality (3.1%, 8/256 versus 2.0%, 5/256, HR 0.70, CI 0.23–2.14), cardiovascular death (0.4%, 1/256 versus 0.8%, 2/256, HR 2.34, CI 0.21–25.80, p=0.49), non-fatal myocardial infarct (0.8%, 2/256 versus 0.4%, 1/256, HR 0.57, CI 0.05–6,32, p=0.65), stroke (0.8%, 2/256 versus 0.8%, 2/256, HR 1.09, CI 0.15–7.76, p=0.93) were not significantly different between patients receiving clopidogrel monotherapy and prolonged DAPT.

Conclusion
Compared to prolonged DAPT, aspirin discontinuation 12–24 months after PCI for high risk patients who received DAPT has similar long-term risk of major adverse cardiac and cerebrovascular events in patients after second-generation DES implantation.

Funding Acknowledgement
Type of funding source: None