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Background Continuous-flow left ventricular assist device (CF-LVAD) patients require anticoagulation with vitamin K antagonists (VKAs). Good versus suboptimal anticoagulation control expressed as high versus low time in target range (TTR) of international normalized ratio results in less clinical events in atrial fibrillation patients. However, data in CF-LVAD patients are lacking. Purpose To study the association between TTR and clinical events in patients with CF-LVAD as destination therapy. Methods Single-centre cohort study in patients receiving CF-LVAD between 2010–2021. Patients were followed from start of VKAs until outcome or end of follow-up. Outcomes were combined major adverse events, thromboembolisms, major bleedings, neurologic events and all-cause mortality. The TTR (low vs. high; 50%) was calculated during the overall study period and over 1-month periods by the Rosendaal-method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox regression with time-dependent covariables, adjusted for confounding. Results 74 patients were included; median age 63 years [interquartile range 58–68], 77% males and 60%ischemic heart failure. During 191 years follow-up, 39 combined major adverse events, 14 thromboembolisms, 21 major bleeding, 22 neurologic events and 38 deaths occurred. For 1-month periods, high TTR was associated with less combined major adverse events (HR 0.3 95% CI 0.2–0.7), major bleeding (HR 0.4 95% CI 0.2–1.1), thromboembolism (HR 0.3 95% CI 0.1–1.3) and death (HR 0.2 95% CI 0.1–0.5) (Table 1). Results considering the overall study period were similar. Conclusion Good anticoagulation compared with suboptimal control during 1-month and the overall study period in CF-LVAD patients with destination therapy is associated with lower rates of combined major adverse events, major bleedings, pump thrombosis and death. Funding Acknowledgement Type of funding sources: None.

Background In the ODYSSEY OUTCOMES trial (NCT01663402), alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowered low-density lipoprotein cholesterol from ∼2.3 mmol/L to ∼1.0 mmol/L at 4 months, reduced the risk of major adverse cardiovascular events (MACE: coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, unstable angina requiring hospitalization), and was associated with fewer deaths compared with placebo in 18924 patients (pts) with recent acute coronary syndrome followed for up to 5 years (yrs). Purpose In the ODYSSEY OUTCOMES trial, the overall safety of alirocumab and placebo was similar, except for an excess of local injection-site reactions with alirocumab. However, the safety among pts eligible for longer follow-up has not been fully explored. Methods The present post hoc analyses describe the efficacy and safety of alirocumab in a pre-specified subgroup (for efficacy) of pts eligible for a minimum of 3 and up to 5 yrs of follow-up. Results There were 8242 pts (43.5%) eligible for ≥3 yrs follow-up, of whom 8228 received at least one dose of study medication, comprising 24,610 pt-years of observation with a median follow-up of 3.3 yrs; 6651 pts were eligible for 3 up to 4 yrs, and 1574 patients were eligible for 4–5 yrs, follow-up. As previously reported in a pre-specified analysis of this subgroup, alirocumab significantly reduced death (4.7% vs. 5.9%; p=0.01) compared with placebo. In the present post hoc analysis, alirocumab also significantly reduced MACE vs. placebo (12.0% vs. 14.2%; Hazard Ratio 0.83 [95% CI 0.74 to 0.94]; p=0.003). In a safety analysis, 3217 (78.3%) vs. 3303 (80.2%) pts in the alirocumab vs. placebo group had at least one adverse event (AE) of whom 27.5% vs. 29.4% had a serious AE (Fig. 1). The frequency of permanent discontinuation of study drug due to AEs, incident diabetes, diabetes worsening or complications, neurocognitive events, elevations of ALT>3, AST>3, bilirubin>2, and creatine phosphokinase>10 times the upper limit of normal, were similar with alirocumab vs. placebo (Fig. 1). While pt-reported local injection-site reactions occurred more frequently with alirocumab, the Kaplan-Meier cumulative incidence for time to first local injection site reaction in the longer-term follow-up subgroup was Conclusions In an 8228-pt subgroup of the ODYSSEY OUTCOMES trial eligible for at least 3, and up to 5 yrs follow-up, the safety of alirocumab was similar to placebo except for an excess of local injection site reactions. This subgroup also derived significant benefit from reduced MACE and death. Thus, alirocumab appears to be both a safe and effective lipid-modifying treatment when used for up to 5 yrs. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi and Regeneron

Introduction Use of serial coronary computed tomography angiography (CCTA) allows for the early assessment of coronary plaque progression which may aid in the prevention of major adverse cardiac events (MACE). However, assessment of serial CCTA is done by using anatomical landmarks for matching baseline and follow-up scans. Recently, a tool has been developed allowing for automatic quantification of plaque progression dynamics in serial CCTA utilizing plaque delineation. Purpose The aim of this study was to determine the thresholds that define whether there is plaque progression and/or regression. These thresholds depend on the contrast to noise ratio (CNR) which is an objective marker for scan quality as the latter impacts the plaque delineation. Methods Thresholds and CNR ratios were determined on 50 patients referred for a CCTA due to thoracic complaints. Two scan phases were selected from each patient in which maximum and minimum differences in plaque delineation were measured. Also, CNR was calculated separately for all three major epicardial coronary vessels. A total of 100 scans were analyzed in the current analysis accounting for a total of 300 coronary vessels. First, vessel and lumen wall delineation was done semi-automatically for all major epicardial coronary vessels. Secondly, manual drawings of 7 regions of interest (ROI) per scan were used to quantify scan quality which was defined using the CNR and calculated for each vessel separately. As plaque differences of two scans at the same moment in time should always be zero, the minimum and maximum difference in plaque delineation was used in these scans along with the CNR in order to create calibration graphs on which a linear regression analysis was performed (Figure 1, charts A & B). Inter-observer measurements were calculated using Pearson's correlation coefficient. Results A total of 300 coronary vessels were assessed at CCTA. Semi-automatic vessel and lumen wall delineation as well as CNR calculation was successful in all cases. Subsequent linear regression analysis performed on the CNR and maximal and minimal plaque delineation differences and taking into account the standard error of the estimate revealed the following formulas for minimum and maximum cut-off values: Max = [(0.660 − (002 × CNR)] + 0.349 Min = [(−1.028 + (0.012 × CNR)) − 0.61 The average CNR values was 13.4±3.6. Average maximum and minimum difference in plaque delineation was 0.7±0.3mm and −0.9±0.6mm respectively. The inter-observer correlation for CNR values was excellent yielding a correlation coefficient of 0.872 (p Conclusion Development of vessel-specific quality-based thresholds for the quantification and visualization of plaque progression dynamics as assessed by serial CCTA seems feasible and may aid in the early detection of atherosclerosis progression. Funding Acknowledgement Type of funding sources: None.

Background/Introduction An anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS) with an interarterial course can be assessed using Computed Tomography Angiography (CTA) for the presence of high-risk characteristics associated with sudden cardiac death. These features include a slit-like ostium, acute angle take-off, and degree of proximal luminal narrowing. However, no robust CTA criteria currently exist to determine the presence of an intramural segment. Purpose The aim of this study is to deduct a method to accurately identify an intramural course of interarterial ACAOS on CTA imaging. Methods All consecutive adult patients with an interarterial ACAOS that were evaluated at the two academic hospitals between January 2010 and July 2019 were screened for inclusion. Inclusion criteria were availability of a preoperative CTA-scan (0.5–1mm slice-thickness) and peroperative confirmation of the intramural segment. Using multiplanar reconstruction of the CTA, the distance between the lumen of the aorta and the lumen of the ACAOS (defined as “interluminal space” (ILS)) was assessed at 2mm intervals along the intramural segment (Figure 1). Results Twenty-five patients (64% female, mean age 46 years, 88% right ACAOS) were included. Analysis showed a mean ILS of 0.69mm±0.15mm at 2mm from the ostium. At the end of the intramural segment where the ACAOS becomes non-intramural, the mean ILS was significantly larger (1.27±0.29mm, p Conclusion(s) The ILS is introduced as novel and robust CTA parameter to identify an intramural course of interarterial ACAOS. An ILS of ≤0.95mm is indicative of an intramural segment with 100% sensitivity and 84% specificity. Funding Acknowledgement Type of funding sources: None.

Background Many patients require arterial revascularization after an index ACS. Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In the ODYSSEY OUTCOMES trial, the PCSK9 inhibitor alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a). Objectives We determined whether the risk of first coronary or any (coronary, peripheral artery or carotid) revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo. Methods The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with ACS and elevated atherogenic lipoproteins despite optimized statin treatment. Treatment effects were summarized by competing-risks proportional hazard models. Results A total of 1559 (8.2%) patients had coronary, 204 (1.1%) peripheral artery, and 40 (0.2%) carotid revascularization after randomization. Alirocumab reduced first coronary revascularization (9.6% vs. 11.3% at 4 years; hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.80–0.97; p=0.01) and any first revascularization (10.8% vs. 13.0%; HR 0.85, 95% CI 0.78–0.94; p=0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm (ptrend Conclusions Alirocumab reduced revascularization after ACS. The risk of revascularization and reduction in that risk with alirocumab were greatest in patients with elevated lipoprotein(a) at baseline. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): SanofiRegeneron Pharmaceuticals

Background While malignant bone sarcoma is rare in the general population, it is the second most common malignancy among children and young adults. (Neo)adjuvant systemic treatment carries a significant risk of cardiotoxicity (CTx) in the form of late-onset left ventricular dysfunction and heart failure. There are several long-term follow up protocols in place for survivors of childhood and adolescent cancers, but when sarcoma is diagnosed at higher age the best follow up practice is less clear and there is little known about the long-term risk and mode of onset of CTx. Purpose To evaluate the effect of age at sarcoma diagnosis on incidence of cardiotoxicity (CTx) and time-to-CTx. Methods This single-center retrospective analysis of CTx of sarcoma treatment was performed at a tertiary sarcoma center in the Netherlands (Leiden University Medical Center, LUMC) among patients with a high-grade osteosarcoma (OS) and Ewing sarcoma (ES). All patients were diagnosed and treated over a 36-year period (1982 and 2018) at LUMC, and followed up until August 2021. The main inclusion criterium was exposure to doxorubicin-containing chemotherapy regimens. The exposure of interest was age at cancer diagnosis with a cut-off for older age at ≥30 years (age30+) The primary study endpoint was incident clinically relevant CTx at follow up, defined as composite of pharmacological heart failure (HF) treatment initiation, HF admissions and ICD implantation. Cause-specific Cox modeling was performed to calculate the hazard ratio (HR) of age group and incidence of both the primary study endpoint and competing risk of all cause death. Results The study population consisted of 556 patients (69.0% OS, 31.0% ES) with a median age at sarcoma diagnosis of 19 [p25-p75: 15–30] years and the majority of patients were male (60.4%). 146 patients were in the age30+ group (26.3%). In a median follow up time of 5.5 [2.0–13.2] years, 27 patients reached the primary endpoint (4.9%). In 7/27 cases an urgent HF hospitalization was the first manifestation of HF and the remaining cases met the primary endpoint due to pharmacological HF treatment imitation. At the end of follow up mortality was 49.3% of patients. The vast majority of patients died of malignancy-related causes (95.6%). When correcting for female sex and sarcoma type, age30+ at sarcoma diagnosis was associated with a near 3.5 fold increased risk of HF compared to when sarcoma was diagnosed below 30: HR 3.39 (95% CI: 1.57–7.31), p=0.019. For the age30+ group whom experienced CTx the time-to-event was shorter compared to those diagnosed below 30 years at: respectively 5.5 years vs. 12.6 years (see Figure 1; Wilcoxon rank-sum test: p=0.012). Conclusions Sarcoma patients above 30 years at diagnosis have an increased risk of CTx and time to development of CTx was significantly shorter. Funding Acknowledgement Type of funding sources: None.