bluuebunny/crossref_metadata_2025_split huggingface dataset:
4945Inclisiran-mediated reductions in Lp(a) in the ORION-1 trial
Authors: Stoekenbroek R M , Ray K K , Landmesser U , Leiter L A , Wright R S , Wijngaard P L , Kallend D , Kastelein J J 
Published: October 2019

Abstract

Background
PCSK9 inhibitors and statins both lower LDL-C by increasing LDL-receptor (LDLR) function. PCSK9 inhibitors lower Lp(a) by 20–30%, whereas statins do not lower Lp(a). The mechanism by which PCSK9 inhibitors lower Lp(a) is unclear. We assessed the role of the LDLR in Lp(a) reductions produced by inclisiran, an siRNA which prevents hepatic synthesis of PCSK9.

Methods
ORION-1 was a phase 2 trial of inclisiran in subjects at high ASCVD risk with elevated LDL-C on optimized statin therapy. Subjects received one dose of inclisiran (200, 300, or 500 mg) or two doses at days 1 and 90 (100, 200, or 300 mg). We assessed the correlations between % change in Lp(a) and LDL-C at Day 180 for the inclisiran groups using Spearman correlation coefficients. We additionally assessed the correlation between % change in Lp(a) and absolute change in LDL-C as a proxy for LDLR expression. Lp(a) was measured using an isoform-independent assay and LDL-C with β-quantification.

Results
ORION-1 included 501 subjects; mean age 63; 65% male; 73% on statins. Median baseline Lp(a) was 37.0 nmol/l (IQR: 11.5–142.0 nmol/l), median LDL-C was 117.0 (IQR: 92.5–149.5 mg/dL). Inclisiran dose-dependently lowered Lp(a) by 14% to 26%. Overall, there was a significant but weak correlation between % change in Lp(a) LDL-C (Spearman coefficient 0.35, p<0.001). This correlation appeared to be stronger at higher inclisiran doses and with repeat dosing (table), as well as in statin-users versus non-users (Spearman coefficient 0.37 vs. 0.21). The correlation between % Lp(a) change and absolute LDL-C change was weaker (0.27, p<0.001).
Correlation coefficients LDL-C – Lp(a) Single-dose groups Two-dose groups Inclisiran overall 200 mg (n=60) 300 mg (n=60) 500 mg (n=60) 100 mg (n=59) 200 mg (n=60) 300 mg (n=59) Lp(a) ∼ % change LDL-C 0.22 0.26 0.22 0.29 0.47 0.51 0.35 Lp(a) ∼ absolute change LDL-C 0.35 0.12 0.04 0.22 0.45 0.24 0.27 Lp(a) ∼ % change LDL-C - Statin users 0.16 0.28 0.28 0.31 0.45 0.55 0.37 Lp(a) ∼ % change LDL-C - Non statin users 0.80 -0.08 0.09 0.10 0.63 0.09 0.21

Conclusion
The dose-dependent correlation between % changes in LDL-C and Lp(a) suggests that the LDLR may be partially responsible for Lp(a) reductions produced by inclisiran. The numerically stronger correlation in statin-users supports the idea that LDL-C may compete with Lp(a) for LDLR binding especially at low LDL-C levels.

Acknowledgement/Funding
The Medicines Company
4949Diverging secular trends in cardiovascular disease 21-year incidence in Swedish men born in 1950–1978
Authors: Aberg D , Adiels M , Lindgren M , Nyberg J , Kuhn G , Schaufelberger M , Toren K , Aberg M , Rosengren A 
Published: October 2019

Abstract

Background
Cardiovascular disease (CVD) mortality is decreasing in Western countries, including Sweden. However, there are reports of increases in incidence in young people with respect to heart failure (HF) and atrial fibrillation (AF). The magnitude and causes of these changes are only partly known.

Aims
We investigated secular trends in incidence in CVD outcomes and their attenuation by changes in body mass index (BMI). The outcomes were risk of acute myocardial infarction (AMI), heart failure (HF) and atrial fibrillation (AF) as well as cardiovascular and all-cause death in a population of Swedish adolescents.

Methods
We followed a cohort of Swedish men enrolled for military service conscription in 1969–1996 (n=1,326,082; mean age=18.3) until December 2016, collected from the national inpatient (IPR) and outpatient registries (OPR). Cox-proportional hazard models were used to analyse the longitudinal change in incidence by with respect to early (0–21 years) of follow-up for subgroups with conscription 1968–1971, 1971–1976, 1976–1981, 1981–1986, 1986–1991, 1991–1996 (with the group born 1971–1976 as reference). Adjustments for potential confounders including BMI were performed.

Results
We found that CVD and all-cause mortality and MI decreased progressively during the follow-up with hazard ratios (HR) of 0.51, 95% confidence interval (CI) 0.43–0.62, HR 0.51 CI 0.57–0.62, and 0.60 CI 0.50–0.72, respectively. In contrast, we found increases in the incidence of HF (HR 1.86, CI 1.48–2.33], and AF (HR 8.26, CI 6.87–9.92). Adjustments for changes in BMI partly attenuated the changes in secular trends. Cubic spline models showed where the changes in secular trends were most prominent.

Conclusion
The incidences of cardiovascular outcomes show diverging secular changes. While MI and cardiovascular mortality are continually decreasing, there is an increase in HF and AF. The associations appear to be partly explained by changes in index BMI over time.

Acknowledgement/Funding
grants from the Swedish Government and the county councils, the ALF–GBG-719761, ALFGBG-751111, Swedish Stroke Association, Göteborg Medical Society
4970Validation of ESC/ERS 2015 guidelines risk score in patients with scleroderma associated pulmonary arterial hypertension (SSc-PAH)
Authors: Fayed H , Ahmad M , Abdelkhalek R , Kotecha T , Brown J , Okonkwo N , Knight D S , Marino P , Schreiber B , Handler C , Denton C P , Coghlan J G 
Published: October 2019

Abstract

Background
The ESC/ERS 2015 guidelines presented a comprehensive risk assessment model with three risk categories based on different clinical and biomarkers data. Low, intermediate and high risk were defined with one-year mortality of <5%, 5–10% and >10%. Different groups suggested different methods of risk assessment based on this model.

Purpose
We applied three different methods to validate the ESC/ERS risk prediction model for one-year survival in SSc-PAH.

Methods
309 patients with SSc-PAH have been diagnosed and managed in our institution from 2006 to 2017. We used three different risk assessment models that have been previously suggested.
1. Suggested by the Swedish group 1: Having a score of 1 (low risk), 2 (intermediate risk) or 3 (high risk) resulting from the average of the sum obtained after grading each of the variables (whichever available) from 1 to 3 according to ESC/ERS guidelines cut-offs for WHO-functional class (FC), 6-minute walking distance (6MWD), NT-Pro BNP, right atrial pressure (RAP) and cardiac index (CI).
2. Suggested by the French group 2: Having none, 1, 2, 3 or 4 of the following low-risk criteria of; FC, 6MWD, RAP and CI.
3. Instead of the invasive data, The French group also suggested the use of a non-invasive model including NT-Pro BNP.
Patients were divided into different risk groups according to data obtained at baseline and at their 6-month follow-up. Survival analysis over a 5-year period was performed using Kaplan-Meier analysis.

Results
Overall median follow-up was 33.3 months. One year survival was significantly different between the risk groups (p<0.001) using either baseline or follow-up data. Applying the French group non-invasive model, almost two thirds of the population ended up in the higher risk group. Whilst applying the Swedish model, two thirds of the population ended up in the intermediate risk group. In all the models used, there were significantly less number of patients in the lower risk groups at onset with improvement of risk profile at follow up. An important advantage of the Swedish model, that it can be calculated even in the presence of missing data, a problem commonly encountered. The French models are easier to calculate but they cannot be applied when there is missing data.
5-year survival with different models

Conclusion
All models used were valuable in risk prediction of SSc-PAH both at onset and at follow up. However, each model has some caveats which should be considered. In all the methods used, the prevalence of high risk criteria is higher amongst the SSc-PAH population which indicates the higher risk profile at the time of diagnosis in comparison to other PAH populations, which could explain the poorer outcome.
5037Drug treatment with beta-blockers and long-term outcome in patients with takotsubo syndrome: results from the takotsubo Italian network
Authors: Silverio A , Citro R , Bossone E , Bellino M , Zito C , Provenza G , Prota C , Iuliano G , Radano I , Polito M V , Baldi C , Novo G , Antonini-Canterin F , Galasso G , Parodi G 
Published: October 2019

Abstract

Background
Although generally considered a benign disease, Takotsubo syndrome (TTS) has recently been associated to a substantially comparable long-term outcome than acute coronary syndrome (ACS). The use of beta-blockers (BB) has been advocated in these patients for secondary prevention after the index event, considering the presumed role of catecholamine in TTS pathophysiology. However, the effect of BB on long-term outcome remains controversial due to the paucity of data and the lack of evidence from randomized studies.

Purpose
To investigate the impact of BB therapy on long-term outcome in patients with TTS.

Methods
The study included all TTS patients enrolled in the Takotsubo Italian Network multicenter registry. Patients were divided in two study groups according to the BB therapy after discharge. The following major adverse cardiac events (MACE) were assessed at the longest available follow-up: cardiac death, TTS recurrence, rehospitalization for cardiac cause, acute or worsening heart failure (HF) and ACS. Also, the composite of cardiac death and rehospitalization as well as the overall MACE were analyzed

Results
The study population included 548 patients (mean age 68.7±11.4 years; 44 males, 8%). Among them, BB treatment was reported in 368 (BB group, 67.2%) and 180 (no-BB group, 32.8%) patients, respectively. The baseline clinical characteristics were substantially comparable among groups with the only exception of COPD, which was prevalent in the no-BB group (10.3% vs 21.7%, p=0.001).
During follow-up (median 18 months 25–75% c.i. 6–29), TTS recurrence was reported in 26 patients (4.7%), ACS in 10 (1.8%), acute or worsening HF in 39 (7.1%), cardiac hospitalization in 71 (13.0%) and cardiac death in 18 (3.3%). The rate of TTS recurrence and ACS was comparable between groups. Conversely, no-BB patients experienced more frequently acute or worsening HF (5.4% vs 10.6%, p=0.034), cardiac rehospitalization (10.9% vs 17.2%, p=0.042) and cardiac death (1.9% vs 6.1, p=0.018) than BB patients. Therefore, the MACE composite endpoint was significantly prevalent in the no-BB group (12.0% vs 20.6%, p=0.010).
Kaplan-Meier curves for the composite of cardiac death and rehospitalization showed a statistically lower survival in the no-BB patients compared to the BB group (p=0.006). Moreover, landmark analysis showed a wider survival benefit in the BB patients after 2 years.

Conclusions
Although in absence of a secondary preventive effect on TTS recurrence, BB may improve the long-term cardiac outcome in patients with TTS. Prospective randomized studies are advisable to confirm these findings.
5195Growth differentiation factor-15 and mortality in suspected or known coronary heart disease patients with diabetes: a subanalysis of the ANOX study
Authors: Unoki T , Suzuki M , Matsuda M , Ajiro Y , Shinozaki T , Sakagami S , Yonezawa K , Shimizu M , Funada J , Takenaka T , Morita Y , Abe M , Akao M , Hasegawa K , Wada H 
Published: October 2019

Abstract

Background
Diabetes is a risk factor for coronary heart disease (CHD), but further risk stratification in patients with diabetes is necessary to improve the prediction and prevention of cardiovascular events and deaths. Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine, which plays an important role in the regulation of the inflammatory response, growth and cell differentiation. Elevated GDF-15 was found in various diseases including diabetes and stable CHD, and was reported to predict mortality and cardiovascular events in general or established CHD population. However, the prognostic value of GDF-15 in suspected or known CHD patients with diabetes is unknown.

Methods
Serum GDF-15 levels were measured in 1,087 suspected or known CHD patients with diabetes undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict cardiovascular events (ANOX) study, and followed up for 3 years. The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, and major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

Results
During the follow-up, 147 patients died from any cause, 47 died from cardiovascular disease, and 94 developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.66; 95% confidence interval [CI], 1.48–1.86), cardiovascular death (HR, 1.63; 95% CI, 1.34–1.99), and MACE (HR, 1.41; 95% CI, 1.20–1.65). Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin-I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (continuous net reclassification improvement [NRI], 0.344; 95% CI, 0.172–0.517; P<0.001; integrated discrimination improvement [IDI], 0.049; 95% CI, 0.026–0.072; P<0.001), but not that of cardiovascular death (NRI, −0.013; 95% CI, −0.300–0.274; P=0.931; IDI, 0.023; 95% CI, 0.003–0.043; P=0.026) or MACE (NRI, 0.059; 95% CI, −0.151–0.268; P=0.583; IDI, 0.005; 95% CI, −0.004–0.015; P=0.244).

Conclusions
In suspected or known CHD patients with diabetes undergoing elective coronary angiography, elevated GDF-15 levels may predict all-cause mortality independent of established risk factors and cardiovascular biomarkers.

Acknowledgement/Funding
The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.
5200Incidental Ventricular Tachycardia: Short and Long-term Prognosis
Authors: Sajadieh G , Sajadieh A 
Published: October 2019

Abstract

Background
The prognostic significance of incidental non-sustained ventricular tachycardia (NSVT) in subjects without manifest heart disease is unknown.

Aim
We aimed to evaluate the short- and long-term prognosis of NSVT.

Methods
Data from 678 subjects from Copenhagen Holter study were analyzed. All had at least 48 hours of Holter recording. NSVT was defined as runs of at least three premature ventricular complexes. All were followed up to 16 years. The primary end-point was defined as a combination of cardiovascular mortality, acute myocardial infarction, coronary revascularization, or stroke.

Results
72 (10.6%) had at least one event of VT. The primary end-point occurred more frequently in patients with NSVT: 38.3 versus 17.7 events per 1000 patient-years: HR and 95% CI: 2.06 (1.37–3.20) after relevant adjustments. In a shorter-term follow-up period of up to two-year there were few events: HR and 95% CI: 1.9 (0.69–5.24). The prognosis in subjects with NSVT was not dependent of the length of the VT (p for interaction 0.9), but of the background risk profile.
Table 1. Results of the Cox proportional Hazard models showing risk of cardiovascular events in different groups of subjects with incidental ventricular tachycardia on ambulatory ECG recording Model 1 p Model 2 p Interaction All VT 2.02 (1.32–3.10) 0.001 1.95 (1.2–3.02) 0.003 VT (3 complexes) 1.79 (0.98–3.27) 0.057 1.84 (1.0–3.38) 0.04 0.91 VT (4–9 complexes) 1.94 (1.13–3.32) 0.016 1.78 (1.06–3.22) 0.029 VT and high risk score* 2.84 (1.79–4.49) <0.0001 2.35 (1.46–3.79) 0.0004 0.22 VT and low-risk score 0.70 (0.26–1.90) 0.49 0.93 (0.34–2.57) 0.88 Model 1: adjusted for sex and age. Model 2: adjusted for sex, age, smoking, diabetes mellitus, systolic blood pressure, LDL cholesterol and NT-proBNP. *Framingham riskscore ≥10 vs <10.

Conclusions
Incidental NSVT in subjects without manifest heart disease is associated with increased risk of mortality and CV-events, however the increased risk is not imminent but with a slow pace over time.

Acknowledgement/Funding
Danish Heart Foundation
5206SICD registry in European paediatric and adult patients with congenital heart defects: preliminary results of the SIDECAR project
Authors: Silvetti M S , Kornyei L , Kwiatkowska J , Tamburri I , Saputo F A , Pazzano V , Fesus G , Di Mambro C , Albanese S , Lovecchio M , Valsecchi S , Drago F 
Published: October 2019

Abstract

Aim
Use of the subcutaneous implantable cardioverter-defibrillator (S-ICD) to prevent sudden cardiac death is increasing. Few data exist on S-ICD in young patients. We report preliminary data from a multicenter European registry of paediatric and young adult patients who underwent S-ICD implantation

Methods
Observational, prospective, non-randomized, standard-of-care study on S-ICD implantation/follow-up in young patients with inherited arrhythmias (IA), cardiomyopathies, and congenital heart defects (CHD).

Results
29 patients (12 CHD, 14 Cardiomyopathies, and 3 IA), mean age 17±6 years, 13 of them <18 years, with body mass index (BMI) 23±4, underwent S-ICD implantation (primary prevention 66%). The first 8 patients underwent a three-incision procedure, the following 21 (72%) a two-incision procedure. No intraoperative complications occurred. Over 19 months median follow-up (25th–75th percentiles, 5–37) 5 patients (17%) received appropriate and 2 (7%) inappropriate shocks. Four patients (14%) had device-related complications requiring surgical intervention: three skin erosions at the superior parasternal incision, one pocket infection. A higher risk of complications was seen in patients who underwent standard procedures [hazard ratio (HR) 14.7, 95% confidence interval (CI) 2.34 to 93.03; P=0.001] and those with BMI <20 (HR 11.06, 95% CI 1.01–121.07; P=0.008).

Conclusion
These preliminary results of a multicenter European paediatric registry suggest that S-ICD is safe and effective with low rates of inappropriate shocks. Improvement of implantation techniques seems associated with better outcome.
5226The majority of 30-day survivors of in-hospital cardiac arrest are alive one-year post-arrest without anoxic brain damage, admission to nursing home or need of in-home care
Authors: Yonis H , Bundgaard K , Noermark Mortensen R , Wissenberg M , Gislason G , Koeber L , Torp-Pedersen C , Mosgaard Larsen J , Hay Kragholm K 
Published: October 2019

Abstract

Background
Survivors of in-hospital cardiac arrest are at risk of anoxic brain damage that can lead to admission to nursing home or need of in-home care. However, studies on long-term outcomes after in-hospital cardiac arrest are scarce with previous research focusing on short term measures such as survival-to-discharge.

Purpose
This study aimed to investigate the composite endpoint of nursing home admission or anoxic brain damage among 30-day survivors of in-hospital cardiac arrest within the first-year post-arrest. As a sub analysis, we also investigated the additional need of in-home care.

Methods
All in-hospital cardiac arrests in 13 Danish hospitals during 2013–2015 were identified from the DANARREST register. Inclusion criteria were indication for a resuscitation attempt and survival to day 30. Patients who, prior to arrest, already lived in a nursing home, and/or had anoxic brain damage were excluded. In the sub analysis patients who received in-home care prior to arrest were also excluded. The DANARREST data was linked to nationwide registries including the National Patient Register and administrative nursing home and home care registries using the Danish Civil Registration Number, a unique personal identification number that is given to every citizen in Denmark.

Results
The primary study population comprised of 454 (26.3%) 30 day-survivors out of 1723 eligible patients. Median age was 67 (Q1-Q3 57–75); 301 (66.9%) were men. In this group, the 1-year risk of anoxic brain damage or nursing home admission was 4.6% (95% CI 2.7%- 6.6%) with a competing risk of death of 15.6% (95% CI 12.3%-19.0%), leaving 79.8% alive without anoxic brain damage or nursing home admission at one-year follow-up (see Figure 1A).
The sub study population comprised of 343 30-day survivors with a 1-year risk of anoxic brain damage, nursing home admission or need of in-home care of 23.6% (95% CI 19.1%-28.1%). The competing risk of death was 7.6% (95% CI 4.8%-10.4%), leaving 68.8% alive without anoxic brain damage, nursing home admission or need of in-home care at one-year follow-up (see Figure 1B).
Figure 1

Conclusion
The majority of 30-day survivors of in-hospital cardiac arrest were alive at one-year follow-up without being diagnosed with anoxic brain damage, admitted to nursing home or without need of in-home care.
5228Identification of reliable clinical variables for early prediction of outcome after out-of-hospital cardiac arrest using algorithm-based machine learning statistical methods
Authors: Johnsson J , Hoerberg S , Holm A , Gustafzelius S , Dankiewicz J , Nielsen N 
Published: October 2019

Abstract

Background
Several factors are known to influence both survival and long-term neurologic function after out-of-hospital cardiac arrest (OHCA). Previous studies have indicated that both pre-hospital circumstances as well as patients' history and clinical status on hospital admission are variables strongly associated with later outcome. This study aimed to identify and evaluate clinical variables for early prediction of outcome for unconscious survivors after OHCA using machine learning statistics analysis.

Methods
The Target Temperature Management (TTM) trial randomized 939 international patients with OHCA of presumed cardiac cause to TTM at 33°C or 36 °C for 24 h in intensive care units (ICUs). Patient outcome were survival and neurological function defined by the Cerebral Performance Category (CPC) scale. This multicentre cohort was used for a post hoc analysis using machine learning statistical analysis.
A Conditional Interference decision forest algorithm was designed for training on the TTM-dataset to perform early prediction of outcome at 180 days.

Results
After ranking all available variables in the TTM-dataset based on their importance for the algorithm to make predictions, we could identify a slimmed list with eleven clinical predictors of a poor outcome including older age, low motor score on Glasgow Coma Scale (GCS), increasing doses of adrenaline, first monitored rhythm not shockable, longer duration of low flow, longer time from cardiac arrest to advanced life support, high BMI (Body Mass Index), low pH, bilateral absence of corneal and pupillary reflex, low initial body temperature and cardiac arrest location at home. Age was overall the most important variable for prediction. Our slimmed prediction model performed slightly worse with an AUC of 0.813 (0.741–0.916) compared to an extended model with all available variables included, AUC = 0.839 (0.778 – 0.886). When using all variables in a comparing logistic regression analysis the mean AUC was a corresponding 0.830 (0.792–0.882).

Conclusion
This algorithm with eleven clinical variables predicted outcome almost as good as a corresponding large model with cardiac arrest patients from the TTM-trial and could be a powerful clinical decision tool for early prediction of outcome after cardiac arrest.