Novartis Pharma Research Articles

Association of beta blocker use with new-onset heart failure and mortality in atrial fibrillation without pre-existing heart failure: the Fushimi AF registry

Abstract Background Heart failure (HF) is one of the major complications in atrial fibrillation (AF). We previously reported that not a few AF patients without pre-existing HF (defined as prior HF hospitalization, New York Heart Association functional class≥2, or left ventricular ejection fraction (LVEF)<40%) subsequently developed new-onset HF. Beta blockers are the established therapy for HF, but it remains unclear whether beta blockers prevent new-onset HF and improve outcomes in AF patients without preexisting HF. Methods In the Fushimi AF registry, 778 of 3,262 patients without pre-existing HF were receiving beta blockers at baseline. We investigated the incidence of new-onset HF defined as cardiac death or HF hospitalization, and all-cause death in a propensity-matched cohort (N=1,198; mean age, 71 years; 39% female; mean LVEF, 66%). Additionally, annual follow-up prescription data before the onset of events were collected in 294 of patients with beta blockers and 395 of those without beta blockers. We also investigated the association of starting or stopping beta blockers with the incidence of new-onset HF and all-cause death. Results During the median follow-up of 5.8 years, new-onset HF and all-cause death occurred in 77 (12.9%) and 118 (19.7%) of patients with beta blockers, and 70 (11.7%) and 131 (21.9%) of those without beta blockers, respectively. Incidence of new-onset HF was comparable between patients with and without beta blockers (Figure 1), and incidence of all-cause death was also comparable between the two groups (Figure 2). In exploratory subgroup analyses, there was no interaction in the association of beta blockers with the incidence of events, except for pulse rate for new-onset HF and left atrial size for all-cause death. Hazard ratio of beta blockers for new-onset HF tended to be lower in patients with higher pulse rates (>84 bpm) (Figure 1), and that for all-cause death was lower in those without left atrial enlargement (Figure 2). Of patients with follow-up prescription data, beta blockers were stopped in 55 (18.7%) and started in 97 (24.6%) patients, respectively. Patients with starting beta blockers had higher pulse rate (78.5±17.3 vs 74.9±13.9 bpm; p=0.03) and more symptomatic AF (58.8% vs 46.0%; p=0.03) compared to those without starting beta blockers, while there was no difference in baseline characteristics between those with and without stopping beta blockers. During the follow-up, the incidences of new-onset HF and all-cause death were also comparable between the patients with and without stopping beta blockers and those with and without starting beta blockers. Conclusion Beta blockers were not associated with the incidence of new-onset HF and all-cause death in AF patients without pre-existing HF. However, the exploratory subgroup analyses suggested the existence of subjects who may benefit from beta blockers. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi Sankyo, Novartis Pharma, MSD, Sanofi-Aventis, and Takeda Pharmaceutical.

Quality indicators of the atrial fibrillation management from the European (EORP) and Asia-Pacific (APHRS) registries

Abstract Background The 2020 ESC guideline for atrial fibrillation (AF) recommends universal quality indicators to identify areas for improvement in clinical practice. It also recommends using clinical registries to monitor clinical practice and identify areas for improvement. We have analysed two large comprehensive prospective clinical registries of patients with AF, the EURObservational Research Programme (EORP) and the Asia Pacific Heart Rhythm Society (APHRS), to compare the achievement of the ESC quality indicators in two major world populations. Methods The EORP and APHRS registries used the same electronic case report forms to collect data. T-test and Chi-squared test were used to compare registries. Logistic regression was used to identify pharmacological rate control therapy predictors in permanent AF. The model was adjusted for age, oral anticoagulation (OAC), EHRA and CHA2DS2-VASc scores, heart rate on the latest ECG and the region of recruitment (Europe or Asia) (STATA Corp, version 13). Results All 11096 EORP patients (59.3% males, age 69±11 years) and 5460 APHRS patients (66.3% males, age 68±12 years) had CHA2DS2-VASc and HAS-BLED scores documented at enrolment. The EORP register included a higher proportion of patients with CHA2DS2VASc ≥2 (81% vs 70%, p<0.001). These patients had similar OAC use (87%) in both registries, but NOAC use was higher in the APHRS (67% vs 34%, p<0.001), while dual antithrombotic use was more common in the EORP (14% vs 8%, p<0.001). The Table lists paraments that may impact OAC prescription. In patients with permanent AF, heart rate (82±20 vs 78±20, p<0.001) and antiarrhythmic pharmacotherapy (9% vs 5%) was higher in the EORP registry. On logistic regression, independent predictors of rate control with antiarrhythmic pharmacotherapy were higher EHRA 3 score (adjusted odds ratio (aOR) 1.8; 95% confidence interval (CI) 1.3–2.5, p<0.001); faster heart rate (aOR 1.01; 95% CI 1.00–1.02, p<0.001); younger age (aOR 0.97; 95% CI 0.96–0.98, p<0.001) and being recruited to the APHRS (aOR 0.56; 95% CI 0.40–0.79, p=0.001). APHRS vs EORP patients with non-permanent AF were less symptomatic (EHRA score I in 56% vs 38%) with less frequent use of antiarrhythmics (25% vs 37%), rhythm-management interventions (32% vs 46%), but higher use of catheter ablation (p<0.001 for all). Conclusion There are significant regional variations in achievement of the ESC quality indicator for AF. The variations may be due to differences in healthcare systems, but they may also reflect the population characteristics. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Since the start of EORP, the following companies have supported theprogramme: Abbott Vascular Int. (2011-2014), Amgen Cardiovascular(2009-2018), AstraZeneca (2014-2017), Bayer AG (2009-2018),Boehringer Ingelheim (2009-2019), Boston Scientific (2009-2012), TheBristol Myers Squibb and Pfizer Alliance (2011-2016), The Alliance DaiichiSankyo Europe GmbH and Eli Lilly and Company (2011-2017), Edwards(2016-2019), Gedeon Richter Plc. (2014-2017), Menarini Int. Op. (2009-2012), MSD-Merck & Co. (2011-2014), Novartis Pharma AG (2014-2017), ResMed (2014-2016), Sanofi (2009-2011), and SERVIER (2009-2018).The Atrial Fibrillation NETwork (AFNET), conducting the registryin Germany, received support from The Bristol Myers Squibb/PfizerAlliance (2014-2018) and the German Centre for CardiovascularResearch (DZHK).

Heart rate and mortality in myocardial infarction: incremental or bimodal correlation?

Abstract Introduction Risk prediction scores adopted in acute coronary syndromes use incremental models to estimate mortality for heart rate (HR) above 60 bpm. Nonetheless, a non-linear, bimodal relationship, with higher event rates at low or high HR, has been described, potentially hampering risk prediction accuracy. Purpose Our aim was to assess the prognostic impact of bradycardia, defined as admission HR <50 bpm, in myocardial infarction (MI) among patients enrolled in a large nationwide registry. Methods Data of patients enrolled between 1999 and 2021 stratified by admission HR were retrospectively analysed. The primary endpoint was in-hospital mortality. The secondary endpoint was a composite of death, cerebrovascular event, and reinfarction. Associations between HR and outcomes were assessed at univariate and multivariable logistic regression analyses, then verified after sequential propensity-score matchings among HR groups. Results 51001 patients (median age 66 years, IQR 56–76) were included. Crude estimates showed a bimodal distribution of primary and secondary endpoints with peaks at low and high HR. Association of HR <50 bpm with mortality was recognised only at primary multivariable logistic regression analysis (OR 1.49; 95% CI 1.01–2.13 p=0.038) but not at multiple sensitivity analyses after exclusion of patients on negative chronotropic therapy. Three sequential propensity-score matching were performed among patients with HR <50 bpm at admission and those with HR 50–75 bpm, HR 76–100 bpm and HR >100 bpm at admission, identifying 1159, 1159 and 1158 matched pairs, respectively. After propensity-score matching, rates of primary and secondary endpoints equalled among groups with HR <100 bpm. Conclusions Bradycardia (HR <50 bpm) at admission in patients with MI identified a group with higher crude rate of adverse events. Nonetheless, the signal supporting an independent association between bradycardia at admission and short-term mortality is weak and was not confirmed after correction for relevant baseline differences by propensity score matching. These findings support the hypothesis that lower HR might not be causative for the worse outcomes, but rather serves as a marker of underlying morbidity. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The AMIS Plus registry is funded by unrestricted grants from the Swiss Heart Foundation and from Abbot AG, Amgen AG, AstraZeneca AG, Bayer (Schweiz) AG, Biotronik AG, Boston Scientific AG, B. Braun Medical AG, Daiichi-Sankyo/Lilly AG, Cordis Cardinal Health GmbH, Medtronic AG, Novartis Pharma Schweiz AG, Sanofi-Aventis (Schweiz) AG, SIS Medical AG, Terumo AG, Vascular Medical GmbH, all in Switzerland, and the Swiss Working Group for Interventional Cardiology. The sponsors did not play any role in the design, data collection, analysis, or interpretation of data.

Comparative effectiveness of sacubitril/valsartan versus angiotensin converting enzyme inhibitors/angiotensin receptor blockers in de novo heart failure patients

Abstract Introduction Effective use of pharmacological therapy in de novo heart failure (HF) patients is key for slowing down the progression of HF. Randomised clinical trials have shown sacubitril/valsartan (sac/val), providing superior benefit over renin angiotensin system (RAS) blockade with angiotensin converting enzyme inhibitors (ACEi) in patients with HF with reduced ejection fraction (HFrEF) including de novo HF patients. However, real world evidence is scarce. Purpose To compare the rate of all-cause hospitalisations in a real world de novo HFrEF US patient population after initiating sac/val or initiating or continuing RAS blockade with ACEi or angiotensin receptor blockers (ARB) within one year of index date. Methods This retrospective, non-interventional cohort study included adult de novo HFrEF patients (left ventricular ejection fraction ≤40%), from the Optum Electronic Health Records, from Jan 2016 to Mar 2020 (study period: Dec 2013–Mar 2021) who were prescribed sac/val or ACEi/ARB within 30 days of a new HF diagnosis. Patients either with any history of HF in the prior two years or with prior sac/val treatment were excluded. Index date was defined as the first prescription of sac/val or ACEi/ARB after a new HF diagnosis (≤30 days prior to index). One-to-two greedy propensity score matching was used to balance the study arms on demographics and clinical covariates (medications, LVEF, selected comorbidities). Negative binomial models were used to compare the primary endpoint between treatment groups and across subgroups of interest. The primary endpoint was the rate of all-cause hospitalisations within one year from index. Treatment groups were stratified by age, sex, race, ethnicity, history of myocardial infarction, comorbidities and prior ACEi/ARB treatment. Statistical analyses were conducted using R and SAS software. Results Prior to matching, 3,290 patients were initiated on sac/val, 47,678 on ACEi/ARB and post-matching there were 3,290 patients on sac/val and 6,580 patients on ACEi/ARB. Patients with prior ACEi/ARB treatment in both the groups were 1,597 and 2,806, respectively. Mean age was 63.5 in sac/val and 63.7 years in ACEi/ARB groups. After propensity-score matching, the annual rate (per person-year) of all-cause hospitalisation was lower in sac/val compared with ACEi/ARB group, with incidence rate ratio (IRR) of 0.81 (95% confidence interval [CI]: 0.74–0.90) ≤1 year from index. Similarly, in the ACEi/ARB treatment naïve subgroup, sac/val treatment led to 20% reduction in the primary endpoint (IRR: 0.80, 95% CI: 0.69–0.92) compared with ACEi/ARB. Amongst subgroups, results were consistent for most, with significant reduction seen in all-cause hospitalisation rates with sac/val treatment vs. ACEi/ARB. Conclusion Treatment with sac/val vs. ACEi or ARB significantly reduced the risk of all-cause hospitalisations in this real-world study supporting the first-line use of sac/val in treating de novo HFrEF patients. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG

Features of clinical complexity in european patients with atrial fibrillation: a report from the ESC-EHRA EORP atrial fibrillation general long-term registry

Abstract Introduction There is increasing concern regarding the burden of clinical complexity, beyond thromboembolic risk, in patients with atrial fibrillation (AF). Also, clinical complexity is heterogenous and entails differential impact on the patients' clinical course. Purpose To explore different complexity features in AF patients in determining differences in clinical management and outcomes. Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. Features of complexity were analysed in the context of the following high-risk groups: i) only CHA2DS2-VASc ≥2; ii) history of stroke/bleeding; iii) chronic kidney disease (creatinine clearance <60 mL/min, CKD); iv) frail (frailty index ≥0.25); v) ≥2 criteria. All these groups were compared to a low-risk group (CHA2DS2-VASc 0–1). We examined use of oral anticoagulant (OAC) and the risks of a composite outcome of all-cause death and major adverse cardiovascular events. Results A total of 10285 patients (mean [SD] age 68.8 [11.5] years, 4107 [39.9%] females) were included in the analysis. Of these, 3944 (38.3%) had only CHA2DS2-VASc ≥2; 412 (4.0%); history of stroke/bleeding; 1480 (14.4%) CKD; 1007 (9.8%) were frail; 1315 (12.8%) had ≥2 criteria; and 2127 (20.7%) were low-risk. After adjustment for age, sex, type of AF and EHRA score, compared to low-risk patients, all the other groups were associated with OAC prescription but with progressively lower odds ratio, while those ≥2 criteria which were least likely prescribed with OAC (Table 1). After a mean (SD) 634.5 (223.0) days of follow-up, a total of 1432 events were recorded. After adjustment for confounders, Cox regression analysis found that all the complexity groups were associated with a higher risk of the composite outcome across the groups (Figure 1). In patients with available data about ABC (Atrial fibrillation Better Care) pathway adherence, the latter adherence was associated a significant incidence rate reduction (IRR) compared to non-ABC adherence in those with ≥2 criteria of clinical complexity (IRR 0.46, 95% CI 0.30–0.71), and in the CKD complexity group (IRR 0.57, 95% CI 0.41–0.81). Conclusions In a large contemporary cohort of European AF patients, features of clinical complexity affect differently prescriptions of OAC. All the subgroups of clinical complexity were associated with a higher risk of adverse outcomes, which were reduced by adherence to ABC pathway. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and PfizerAlliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), and Vifor (2019–2022).

Heart failure and cardiovascular outcomes in european patients with atrial fibrillation

Abstract Background Heart failure (HF) has an intimate bidirectional association with atrial fibrillation (AF). Few data are available about the impact of HF phenotypes (HF with preserved ejection fraction, HFpEF; HF with mildly reduced ejection fraction, HFmrEF; HF with reduced ejection fraction, HFrEF) as predictors for adverse outcomes in AF patients. Purpose To investigate the association of HFpEF, HFmrEF and HFrEF with adverse outcomes in a large contemporary cohort of European AF patients and evaluate the effect of EF throughout its entire spectrum. Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. HF patients were categorized according the three phenotypes and compared to those without HF (“non HF”). Main outcome was a composite outcome of all-cause death and major adverse cardiac events (MACE). Results Among the original 11,096 AF patients enrolled, 9857 (88.8%) were included in this analysis (median age 71 years, interquartile range [IQR 63–77], 40.1% females) with median EF 55% [IQR 45–61%] and CHA2DS2-VASc 3 [2–4]). In this cohort, 5935 (60.2%) were non HF patients, and 3240 (32.9%) had HF patients (with HF status and EF values data available). Accordingly, 1662 (51.2%) were categorized as HFpEF; 523 (14.1%) were HFmrEF; and 1235 (35.1%) were HFrEF. After a median follow-up of 731 days [IQR 690–748], the composite outcome was significantly higher throughout HF categories (HFpEF 19.0%, HFmrEF 21.8% and HFrEF 29.6%, compared to non HF 10.7%; p<0.001). In a fully adjusted multivariate Cox regression, HF phenotypes were associated with a progressively higher risk for the composite outcome (HFpEF HR 1.45 [95% CI, 1.23–1.70]; HFmrEF HR 1.82 [95% CI, 1.45–2.3]; HFrEF HR 2.51 [95% CI, 2.14–2.95], when compared to non HF patients). Considering EF in its continuous spectrum, an adjusted regression curve analysis found that progressively lower EF was associated with a progressively higher risk for the composite outcome, both in HF and overall AF patients (Figure 1, left and right panel, respectively). Conclusions Over a two-years follow-up, in a large contemporary cohort of European AF patients, HF phenotypes were associated with a progressively higher risk for adverse outcomes. Lower EF values increased the risk of adverse outcomes both in HF patients and overall AF patients, irrespective of HF phenotype status. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), and Vifor (2019–2022).

Communication disconnect concerning erectile dysfunction in male heart failure patients: cardiologists and GPs need to talk about sex

Abstract Background Heart failure (HF) and erectile dysfunction (ED) share risk and pathogenetic factors manifesting in a higher prevalence of ED in male HF patients. Despite being a recognized comorbidity, scientific research in this field is limited. Purpose This research aims to better understand the patient journey from a patients' as well as health care professionals' (HCP) perspective in terms of communication, education and ED treatment as recognized concomitant disease in HF patients. Methods Data was collected using two independent online surveys between Nov 21 and Jan 22 from diagnosed male HF patients (N=927) and HCPs including general practitioners (GP), cardiologists and internists (N=78) on quality of life (QoL) with focus on sexual life. As part of the patient survey, male HF patients with ED (N=176) were asked to provide further information about their experiences and ED-related communication with HCPs. Results Male HF patients reported their sexual life as being important (56%*) and their sexual health impacting QoL, with 43% of all men asked (N=927) being unsatisfied with their sexual life. Focusing on HF patients with ED (N=176), half was not aware of the link between HF and ED. Only 33% of male HF patients stated that they were informed about a potential link by their HCP, equally distributed to GPs, cardiologists and urologists. HCPs in turn reported that only 20% of their patients proactively consult them, but the majority of male HF patients with ED (69%) stated that they feel left alone and wish for more personal exchange regarding the topic of ED with a doctor (74%). HCPs reported awareness of strong ED burden in 70% of their male HF patients. In contrast to the patients' perspective, 56% of HCPs report that they do address the topic of ED to their HF patients. Top ranked reason for not addressing the topic of ED from HCP side were the assumption and/or knowledge that patients feel uncomfortable talking about ED. Interestingly, only 7% of male HF patients with ED indeed indicated feeling uncomfortable. Despite their pronounced sexual dissatisfaction only 40% of male HF patients with ED indicated that they talk to a doctor about ED treatment options. In consequence, only 22% of them take prescription drugs. More frequently, HCPs reported that about one third of their patients are non-compliant with HF medication due to ED highlighting the high importance of sexual health for patients' QoL. Conclusions We identified a communication disconnect between HCPs and HF patients regarding ED. As patients' QoL is strongly affected by sexual health, they wish for more personal exchange and information. There is a strong need to proactively address the topic of ED by cardiologists and GPs as the first point of contact for HF patients. New ideas for tools generating a better understanding and more confident conversations about HF and ED are warranted. *On a scale from 1 = “not important” to 10 = “very important” rated ≥7. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH

ABC adherence and impact of optimal medical therapy in heart failure patients with atrial fibrillation

Abstract Background Heart failure (HF) has close association with atrial fibrillation (AF). The ESC guideline recommended Atrial fibrillation Better care (ABC) pathway aims to reduce major cardiovascular adverse outcomes with an integrated care approach. Optimal medical treatment (OMT) represents the cornerstone in HF management. Purpose To investigate the variables affecting OMT treatment and its impact, in conjunction with ABC pathway adherence (vs non-adherence, ie.no ABC), in a large contemporary cohort of European AF patients with HF enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. Methods OMT was defined as treatment with Angiotensin-converting-enzyme inhibitors (ACE-i)/ Angiotensin receptor blockers (ARBs) with Beta-Blockers and/or Mineralocorticoid receptor antagonists (MRAs), and compared to non-OMT adherence (“no OMT”). A logistic regression analysis explored factors associated with OMT adherence. We identified three patient groups: (i) HF with no OMT/no ABC; (ii) HF with OMT/no ABC; (iii) HF with OMT/ABC. Primary outcome was a composite outcome of all-cause death and major adverse cardiac events (MACE). Results Among the original 11096 patients enrolled, 9857 (88.8%) were included in this analysis. Among these, 3819 (38.7%) had HF. Compared to non HF patients, those with HF were older, more likely female, had more comorbidities and higher thromboembolic risk. OMT prevalence was 2228/3819 (58.3%), while ABC adherence was 23.3%. On logistic multivariable regression, increasing age, higher BMI and higher frailty index were associated with OMT adherence, while male sex, anemia, renal disease and EHRA II–IV were inversely associated with OMT adherence. According to three HF groups, the rates of composite outcome progressively decreased (HF with no OMT/no ABC 26.4%; HF with OMT/no ABC 24%, HF with OMT/ABC 19%; p<0.001). Kaplan Meier curve showed progressively lower cumulative risk for the composite outcome across the three groups with the lowest risk among HF patients with OMT/ABC (Log-rank: p=0.002) [Figure 1]. Adjusted Cox regression analysis showed that when compared to HF with no OMT/no ABC group, there was a progressively lower risk with OMT and/or ABC adherence (HF with OMT/no ABC: HR 0.81 [95% CI, 0.64–1.02]; HF with OMT/ABC: HR 0.68 [95% CI, 0.5–0.92]). Conclusions After two years of follow-up, in a large contemporary cohort of European AF patients with HF, OMT adherence was suboptimal, being influenced by several clinical factors, determining a low adherence to the ABC pathway. OMT alone showed a non-significant reduction in composite outcome events. Conversely HF patients managed with OMT in the context of ABC pathway adherence showed the best reduction in risk of adverse outcomes. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), and Vifor (2019–2022). - I agree that this information can be anonymised and then used for statistical purposes only

Living with heart failure: quality of life, particularly sexual life, is impaired by emotional burden as reported by patients

Abstract Background Symptoms of heart failure (HF) include shortness of breath and limited exercise capacity as a result of fluid retention and circulatory disorders. Life expectancy of HF patients has improved, mainly driven by current treatment modalities. The burden of HF in terms of quality of life (QoL) and emotional well-being is frequently neglected and is less well described than typical HF symptoms. Purpose The aim of this study is to better understand the impact of HF on patients' QoL and emotional well-being from the patients' perspective. Methods Data on disease perception and physical as well as emotional burden was collected using an online survey from Nov to Dec 21 from patients with HF diagnosis (Nfemale=830; Nmale=927). Results Overall, the majority of HF patients considered being capable of fulfilling everyday routines as highly important. In detail, 87% of HF patients rated taking care of themselves, 82% running the household independently, 83% mobility outside the house and 74% social life with highest importance*. Impairments in the same QoL determining aspects from above showed a bimodal distribution of HF patients meaning that they were either highly affected or not affected at all. Male and female HF patients rated QoL aspects in terms of importance and impairment equally, except sexual life importance and sexual impairments, which were ranked higher by men (56% vs. 42%*, 39% vs. 32%§, respectively). Being asked about their biggest concern regarding HF via an open-ended question, death was the most commonly reported term. However, 20% indicated social and emotional worries as their first concern. Indeed, HF patients were frequently emotionally affected and almost every second HF patient stated considerable restrictions of their daily obligations and every third of their social life due to emotional problems. Patient-reported emotions were being worried (53%#), listless/without energy (47%#), fatigue (45%#) and/or afraid (42%#). Interestingly, the fraction of HF patients being unsatisfied with their sexual life was larger when patients indicated feeling emotionally affected (worried, listless, fatigue, afraid). On the other hand, HF patients indicating no negative emotions were more satisfied with their sexual life highlighting the importance of sexual health contributing to QoL. Conclusion(s) The emotional burden experienced by HF patients is as high as their physical impairments culminating in considerable restrictions of their daily routines due to emotional problems. Additionally, emotional well-being is strongly linked with sexual satisfaction. *On a scale from 1 = “not important” to 10 = “very important” rated ≥7. §On a scale from 1 = “not affected” to 10 = “no activity possible” rated ≥7. #On a scale of 1 = “never” to 10 = “very often” rated ≥7. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma GmbH

Factors associated with progression of atrial fibrillation and impact on all-cause mortality: an ancillary analysis from the ESC-EHRA EURObservational Research Programme in Atrial Fibrillation General

Abstract Background Paroxysmal atrial fibrillation (AF) often shows a natural progression towards more sustained forms of the arrhythmia. Real-world data on clinical factors associated to AF progression and its impact on long-term outcome are limited. Purpose To investigate the factors associated with progression of AF and its impact on all-cause mortality in a contemporary cohort of European AF patients Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. Patients with paroxysmal AF at baseline or first detected AF who underwent successful cardioversion were included. Patients with known rhythm status at 1-year were then stratified into two groups: (i) No AF progression and (ii) AF progression (as defined by transition to persistent or permanent AF). All-cause mortality at 2-year of follow-up was the primary outcome of the analysis. Results A total of 2688 patients were included (median age 67 years, interquartile range [IQR] 60–75, females 44.7%, CHA2DS2VASc score median 3 [1–4], HASBLED median 1 [1–2]). After 1-year of follow-up 2094 (77.9%) patients showed no AF progression while 594 (22.1%) developed AF progression. On multivariable logistic regression analysis, no physical activity (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.02–1.78), valvular heart disease (OR 1.63, 95% CI 1.23–2.15), left atrium diameter (OR 1.03, 95% CI 1.01–1.05) and left ventricular ejection fraction (OR 0.98, 95% CI 0.97–1.00) were independently associated with AF progression at 1-year. At the end of 2-year of follow-up, death occurred in 80/2621 (3.1%) patients. Kaplan-Meier analysis showed a lower cumulative survival from all-cause mortality in patients with AF progression compared to non-progression AF patients (Log Rank p=0.01, Figure 1). On multivariable Cox regression analysis, adjusted for age, sex, heart failure, coronary artery disease, hypertensions, diabetes mellitus, previous thromboembolic events, peripheral artery disease, chronic kidney disease and use of oral anticoagulants, patients with AF progression had an independently higher risk for all-cause mortality (adjusted hazard ratio [aHR] 1.77, 95% CI 1.09–2.89). Conclusions In a contemporary cohort of European AF patients, a substantial number of patients progressed to sustained AF within 1 year. Clinical factors related to atrial structural remodeling were independently associated with arrhythmia progression. AF progression was associated with an increased risk of all-cause mortality. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), and Vifor (2019–2022).

Anaemia and adverse outcomes in European patients with atrial fibrillation: a report from the ESC-EHRA EORP atrial fibrillation general long-term registry

Abstract Background Anaemia is an independent predictor of atrial fibrillation (AF) and a common comorbidity. Real world data on the impact of anaemia on clinical outcomes, and on the benefits and risks of oral anticoagulation (OAC) are limited. Purpose To investigate the association of different degrees of anaemia with adverse outcomes in a cohort of European patients with AF. Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry with baseline hemoglobin (Hb) values. Patients were stratified according to World Health Organization (WHO) definition of anaemia: (i) No anaemia (Hb≥12.0g/dl for women and Hb≥13.0g/dl for men), Mild anaemia (Hb 11.0–11.9g/dl for women and Hb 11.0–12.9g/dl for men), and moderate-severe anaemia (Hb ≤10.9 g/dl for both sexes). Primary outcomes were all-cause death, major adverse cardiac events (MACE, as the composite of any thromboembolism (TE)/acute coronary syndrome/cardiovascular death) and major bleeding. Results From the original 11,096 AF patients enrolled in the Registry, 7767 (69.9%) were included in the present analysis (median age 70 years, interquartile range [IQR] 62–77, males 58.3%, CHA2DS2VASc score median 3 [2–4], HAS-BLED median 2 [1–2]). A total of 5973 (76.9%) patients did not have anaemia, 1156 (14.9%) had mild anaemia, and 638 (8.2%) had moderate/severe anaemia. Patients with anaemia were more likely to have more comorbidities, frailty, permanent AF and polypharmacy (≥5 drugs). Overall, 318 (18.4%) patients with anaemia and an indication for anticoagulation [i.e. CHA2DS2-VASc≥1 (males), or ≥2 (females)] did not receive any OAC. After a median (IQR) follow-up of 730 (692–749) days, all-cause death was 10.5% and there were 841 (11.6%) MACE and 186 (2.5%) major bleeds. Kaplan–Meier analysis showed a higher cumulative risk for patients with moderate-severe anaemia for all the outcomes considered (Figure) (Log Rank tests, all p<0.001). Adjusted Cox regression analyses revealed that patients with mild and moderate-severe anaemia had a higher risk for all-cause death (adjusted hazard ratio [aHR] 2.02, 95% confidence interval [CI] 1.71–2.40 and aHR 2.39, 95% CI 1.97–2.91, respectively), MACE (aHR 1.44, 95% CI 1.17–1.76 and aHR 1.64, 95% CI 1.30–2.07 respectively), and major bleeding (aHR 1.52, 05% CI 1.02–2.25 and aHR 3.73, 95% CI 2.59–5.37, respectively). Among patients with moderate-severe anaemia, use of OAC was associated with lower risk of all-cause mortality (HR 0.64, 95% CI 0.46–0.89) and MACE (HR 0.55, 95% CI 0.36–0.84), without a significant increased risk of major bleeding (HR 0.81, 95% CI 0.43–1.52). Conclusions In a large contemporary cohort of European AF patients, almost 25% have concomitant anaemia which is associated with an increased risk for all-cause mortality, MACE and major bleeding. Use of OAC was associated with a lower risk of all-cause mortality in patients with moderate-severe anaemia, without significant increased risk of major bleeding. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Since the start of EORP, the following companies have supported the programme: Abbott Vascular Int. (2011–2021), Amgen Cardiovascular (2009–2018), AstraZeneca (2014–2021), Bayer (2009–2018), Boehringer Ingelheim (2009–2019), Boston Scientific (2009–2012), The Bristol Myers Squibb and Pfizer Alliance (2011–2016), The Alliance Daiichi Sankyo Europe GmbH and Eli Lilly and Company (2011–2017), Edwards (2016–2019), Gedeon Richter Plc. (2014–2017), Menarini Int. Op. (2009–2012), MSD-Merck & Co. (2011–2014), Novartis Pharma AG (2014–2020), ResMed (2014–2016), Sanofi (2009–2011), SERVIER (2010–2021), and Vifor (2019–2022)

Itch-free state in patients with atopic dermatitis treated with ruxolitinib cream: A pooled analysis from two randomized phase 3 studies

Itch-free state in patients with atopic dermatitis treated with ruxolitinib cream: A pooled analysis from two randomized phase 3 studies

O-09: DURABLE ENGRAFTMENT AFTER PHARMACOLOGICAL PRE-TRANSPLANT IMMUNOSUPPRESSION FOLLOWED BY REDUCED-TOXICITY MYELOABLATIVE HAPLOIDENTICAL STEM CELL TRANSPLANTATION IN HIGHLY HLA-IMMUNIZED ADULTS WITH SICKLE CELL DISEASE

Purpose: Sickle cell disease (SCD) is the most common genetic disorder worldwide and despite advances in best supportive care, remains a disease with high morbidity and mortality. Allogeneic stem cell transplantation (AlloHSCT) is a curative treatment modality. Reports in adults are limited because of the high risk of transplant related toxicity, graft rejection and the lack of suitable donors. The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to AlloHSCT. Antibodies against donor-specific HLA (DSA) which are frequently detected in multi-transfused SCD patients increase the risk of engraftment failure in HLA mismatched AlloHSCT. Materials and methods: We report the results of five patients with severe SCD (22, 46, 27, 30 and 30 years old) and DSA who underwent an unmanipulated haploidentical bone marrow transplantation (HaploBMT) after a RT-MAC regimen. The conditioning regimen consisted in rabbit antithymoglobuline (ATG), fludarabine (flu) and busulfan. GVHD prophylaxis was performed with PT-Cy, cyclosporine A and mycophenolate mofetil. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immunosuppression (PTIS) phase was added prior to the conditioning regimen. This initially was based on flu in combination with dexamethasone and was later modified to include cyclophosphamide (cy) and ATG in patients with CNS involvement. The desensitization protocol of DSA consisted in rituximab, velcade and plasmapheresis followed by high dose intravenous immunoglobulins. (Figure 1) Importantly, the patients were highly immunized with severe hemolytic crises and high DSA titers (range, MFI 2000 – 10003); two patients had also a history of cerebrovascular complications whereas the 46 years old woman with sickle cell specific multi-organ damage. All donors were first degree family members (sibling, parent, child). Results: All patients successfully engrafted with neutrophil reconstitution on days 26, 31, 16, 24 and 21 days (median 23 days), respectively. The procedure was well tolerated with only mild toxicity. None of the patients developed acute GVHD. One patient developed moderate chronic skin GVHD at day +489 after HaploBMT with rapid response to conventional immunosuppressive therapy. After a follow-up of 2323, 1770, 994, 962 and 263 days (median 994 days) respectively, chimerism analysis and detection of hemoglobin S confirmed sustained donor engraftment. All patients were free of any pain symptoms with excellent quality of life. Conclusion: Our report shows that HaploHSCT after a busulfan-based RT-MAC regimen is feasible and safe and allows stable long-term engraftment and excellent disease control. Graft failure may be overcome by adding a PTIS phase prior to the conditioning regimen. Further studies are necessary to confirm these promising results and allow a widened access of this platform technology to patients with high-risk sickle cell disease.Desensitization procedure E. BERNIT declares a conflict of interest: Consultancy, Expert: NOVARTIS PHARMA

P-025: ABNORMAL MITOCHONDRIA RETENTION IN MATURE RED BLOOD CELLS OCCURS NOT ONLY IN SS BUT ALSO SC PATIENTS AND IS ASSOCIATED WITH HEMOLYTIC MARKERS

Purpose: Sickle cell disease (SCD), the most frequent genetic disease worldwide, results from a unique point mutation leading to the synthesis of the abnormal hemoglobin S (HbS). Under hypoxic condition, HbS polymerization causes a mechanical distortion of red blood cells (RBCs) called sickling, which is accompanied by a decrease of their deformability and their life span. SCD is characterized by a wide variability of clinical expression and a complex pathophysiology including vaso-occlusive processes, intravascular hemolysis as well as pro-inflammation, pro-coagulant and vaso-constrictive states. Recently, the abnormal mitochondria retention in mature RBCs has been documented in small series of SS patients but the biological consequences of this abnormality have not been fully documented and not been documented in other sickle cell syndromes. In the present study, we analyzed mature RBC mitochondria retention in both SS and SC patients, the second most frequent sickle cell syndrome, taking into account the biological/clinical features associated with these abnormal RBCs. Materials and methods: Eighty-nine adult SCD patients were included: 35 SS patients treated with hydroxyurea (HU), 15 SS patients not treated with HU and 39 SC patients. All of them were at steady-state and regularly followed by the sickle center of Guadeloupe. Twenty-one Guadeloupean adult controls (AA) were also included. Mature RBCs containing mitochondria were identified by flow cytometry using MitoTracker® probe as well as thiazole orange and anti-CD71 antibody to discriminate total and stress reticulocytes respectively. Correlations between the percentage of mature mitochondria+-RBCs and the following parameters were then analyzed: RBC deformability (Ektacytometry), reticulocytes (both total and CD71+) counts and levels of hemoglobin, total bilirubin, aminotransferase aspartate and lactate dehydrogenase levels using routine procedures. The impact of splenic function was evaluated using Howell-Jolly bodies, assessed by classic May-Grünwald Giemsa smears, as a marker of splenic dysfunction. We also analyzed the relationships between mitochondria+-RBCs and HU treatment as well as the rates of hyper vaso-occlusive (painful vaso-occlusion, acute chest syndrome, osteonecrosis) and hyper hemolytic (micro/macro-albuminuria, leg ulcer) complications. Results: Abnormal mitochondria+ RBCs were detected not only in SS but also in SC patients, although at a less extend. In both sickle cell syndromes, positive correlations with mitochondria+ RBCs were detected with hemolysis markers (percentage of total and stress reticulocytes). In addition, a negative relationship with hemoglobin level was detected in SS patients. A negative correlation was also detected between these abnormal mitochondria+ RBCs and RBC deformability. In contrast, no association between the presence of this RBC sub-population and clinical manifestations, hydroxyurea treatment or Howell-Jolly bodies was detected. Conclusion: In the present report, we demonstrated that abnormal retention of mitochondria in mature RBCs occurred not only in SS but also in SC patients. We also presented evidence that this phenotype could be related to hemolysis rate. Further studies are warranted to reveal the molecular mechanisms involved. E. BERNIT declares a conflict of interest: Consultancy, Expert: for NOVARTIS PHARMA SAS

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

†Efficacy and Safety of Inclisiran in Patients with Established Cerebrovascular Disease: Pooled Post hoc Analysis of the Phase 3 ORION-9, ORION-10, and ORION-11 Randomized Controlled Trials

<h3>Lead Author's Financial Disclosures</h3> Wolfgang Koenig, MD has received consulting fees and lecture fees from AstraZeneca, Novartis and Amgen; consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Genentech, Esperion, OMEICOS, Novo Nordisk, LIB Therapeutics, Kowa, Corvidia Therapeutics and Daiichi Sankyo; lecture fees from Berlin- Chemie, Bristol-Myers Squibb and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr. Beckmann Pharma. <h3>Study Funding</h3> Novartis Pharma AG, Basel, Switzerland. <h3>Background/Synopsis</h3> Patients with hyperlipidemia and established cerebrovascular disease (CeVD) are at increased risk of future strokes or other cardiovascular events (1). In ischemic stroke survivors, statins and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce recurrent cardiovascular events, including stroke (2,3). With guidelines advocating increasingly lower low-density lipoprotein cholesterol (LDL-C) goals, adding lipid-lowering therapies to statins may be needed. Inclisiran, a first-in-class small interfering RNA targeting PCSK9 messenger RNA, when added to maximally tolerated statin therapy for patients with established CeVD, may provide further LDL-C lowering, with a convenient, infrequent dosing schedule (4). <h3>Objective/Purpose</h3> To assess the efficacy and safety of inclisiran in patients with established CeVD. <h3>Methods</h3> This was a post hoc analysis of patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease or its risk equivalents and established CeVD (ischemic stroke, carotid artery stenosis by angiography or ultrasound greater than 70%, and/or percutaneous or surgical carotid artery revascularization) from ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800), randomized 1:1 to receive inclisiran sodium 300 mg (equivalent to 284mg inclisiran) or placebo at Day 1, Day 90, and 6 monthly thereafter to Day 540. Evaluations included LDL-C percentage change from baseline to Day 510 and corresponding time-averaged percentage change from baseline after Day 90 to Day 540; safety was assessed over 540 days. <h3>Results</h3> Of 202 patients with established CeVD at baseline, 90.0% (99/110) of patients receiving inclisiran and 84.8% (78/92) on placebo reported prior ischemic stroke; others reported prior carotid artery stenosis and/or carotid revascularization (Table 1). Mean (95% CI) placebo- corrected LDL-C percentage change from baseline at Day 510 with inclisiran was −55.2% (−64.5 to −45.9); corresponding time-averaged change from baseline between Days 90 and 540 was −55.2% (−62.4 to −47.9) (P less than 0.0001 for both; Table 2). Treatment-emergent adverse events (TEAEs) and serious TEAEs were more frequent with inclisiran vs placebo. Clinically relevant injection site TEAEs were more frequent with inclisiran (3.6% [4/110]) vs placebo (0% [0/92]) and none was severe. Few patients had clinically relevant laboratory measurements (Table 2). <h3>Conclusions</h3> In patients with established CeVD, twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided a sustained additional LDL-C reduction of ∼55% and a modest increase in mild/moderate injection site TEAEs. The cardiovascular benefits of inclisiran in patients with established CeVD are being evaluated in ongoing trials.

Characterization of Inclisiran Use in Real World: Prescription Data from Germany

<h3>Lead Author's Financial Disclosures</h3> Raquel Lahoz is an employee of Novartis Pharma AG, Basel, Switzerland, and owns Novartis shares. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Despite the availability of effective low-density lipoprotein cholesterol (LDL-C) lowering drugs, ∼80% of patients with established ASCVD fall short of achieving and maintaining LDL-C levels <70 mg/dL, highlighting the need for innovative new LDL-C lowering therapies. Inclisiran is a novel small-interfering RNA (siRNA) that effectively reduces circulating LDL-C. Administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months, inclisiran has been approved by the European Medicines Agency (EMA) in December 2020 for adult patients with hypercholesterolemia as an adjunct to diet who require additional lowering of LDL-C despite receiving other lipid-lowering therapies and by the Food and Drug Administration (FDA) in December 2021. <h3>Objective/Purpose</h3> This study aimed to assess real-world patient characteristics, adherence and persistence for patients being initiated with inclisiran in Germany. <h3>Methods</h3> This retrospective non-interventional study used the IQVIA LRx prescription database and included adult patients being initiated with inclisiran treatment between February 2021 and October 2021 with a 6-month lookback period. For the adherence and persistence analyses, a subgroup of patients with a first inclisiran prescription recorded between February and June 2021 was selected, allowing for at least 4 months follow-up, up to October 2021. <h3>Results</h3> A total of 697 patients receiving at least one dose of inclisiran between February- October 2021 were included in this study. Mean age of patients was 63 years (50% females) and 81% were ≥ 55 years old. Majority of patients were prescribed inclisiran by their nephrologists (42%) and cardiologists (30%). Of the 334 patients receiving their first inclisiran dose between February-June 2021, the second dose was also recorded for 257 (77%) patients until the time of the analysis; median time between the two doses was 3 months and 91% (233) of patients received the second dose within 4 months of treatment initiation. <h3>Conclusions</h3> This study shows early results from one of the first real-world studies describing the characteristics of patients being initiated with inclisiran with majority returning for their second dose within 4 months. Future real-world studies with longer follow-up are needed to evaluate the long-term adherence and persistence as well as effectiveness of inclisiran.

†Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled Post hoc Analysis of the phase 3 ORION-9, ORION-10, and ORION-11 Randomized Controlled Trials

<h3>Lead Author's Financial Disclosures</h3> Wolfgang Koenig, MD has received consulting fees and lecture fees from AstraZeneca, Novartis and Amgen; consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Genentech, Esperion, OMEICOS, Novo Nordisk, LIB Therapeutics, Kowa, Corvidia Therapeutics and Daiichi Sankyo; lecture fees from Berlin- Chemie, Bristol-Myers Squibb and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr. Beckmann Pharma. <h3>Study Funding</h3> Novartis Pharma AG, Basel, Switzerland. <h3>Background/Synopsis</h3> Approximately 25% of patients with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD) involving 2 or more coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular events (MACE) and death. Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDL-C) concentrations and MACE incidence in patients with PVD. Inclisiran is a small interfering RNA agent targeting PCSK9 messenger RNA that is well tolerated and provides effective and sustained LDL-C reductions. <h3>Objective/Purpose</h3> To describe the effect of inclisiran vs placebo in patients with and without PVD. <h3>Methods</h3> This was a post hoc analysis of patients with heterozygous familial hypercholesterolemia or ASCVD or its risk equivalents randomized 1:1 to 300mg inclisiran sodium (equivalent to 284mg inclisiran) or placebo at baseline, Day 90, and 6 monthly thereafter in ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800). Evaluations included LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 to Day 540, with both evaluated by PVD presence or absence, and safety over 540 days. <h3>Results</h3> Baseline characteristics for 470 patients (13.6%) with PVD and 2984 (86.4%) without PVD were generally balanced between treatment arms in both groups, with higher cardiovascular risk factors and lower LDL-C concentrations in patients with PVD (Table 1). Mean (95% CI) placebo-corrected LDL-C percentage changes from baseline to Day 510 with inclisiran were −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in those without (Table 2). Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were similar between treatment arms irrespective of PVD status, although reported TESAEs trended higher with PVD in both treatment arms (Table 2). Clinically relevant injection site TEAEs were more frequent with inclisiran vs placebo in both groups; all were mild or moderate. Few patients had clinically relevant laboratory measurements (Table 2). <h3>Conclusions</h3> Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in patients with ASCVD irrespective of their PVD status, with a safety profile similar to that of placebo except for a modest increase in mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in patients with PVD, which was likely due to their more advanced disease. Since patients with PVD are at high risk of cardiovascular events, intensive LDL-C lowering may be beneficial to reduce this risk.

116-OR: Changes in Glucose Tolerance and Related Factors after Renal Transplantation in Recipients with Impaired Glucose Tolerance

Background and Aims: Our previous study revealed that more than half of patients with impaired glucose tolerance (IGT) before renal transplantation improved to normal glucose tolerance after transplantation. However, the mechanism was not clear. This study aimed to investigate whether changes in glucose tolerance were associated with insulin secretion and resistance in Japanese renal transplant recipients diagnosed with IGT before transplantation. Materials and Methods: We analyzed data for 179 patients ≥20 years of age who received their first renal transplantation in our hospital from April 2005-October 20 and had no history of diabetes before transplantation. A total of 54 recipients who received the oral glucose tolerance test (OGTT) before and 1 year after transplantation and were diagnosed with IGT before transplantation. Patients were divided into two groups according to negative or positive changes in area under the blood glucose curves from 0-120 min after ingestion: improved group and non-improved group, respectively. Insulin secretion was estimated by the insulin secretion sensitivity index-2 (ISSI-2) and insulin sensitivity was estimated by the Matsuda index (MI) and homeostasis model assessment of insulin resistance (HOMA-IR) . Results: Thirty and 24 patients were in the improved and non-improved groups, respectively. ISSI-2 significantly increased from 1.67±0.44 to 2.00±0.60 (P&amp;lt;0.01) after transplantation in the improved group, but not in the non-improved group. ΔISSI-2 was significantly associated with the 60-min blood glucose level of the OGTT and ISSI-2 level before transplantation (β=0.01, P&amp;lt;0. and β=−0.59, P&amp;lt;0.01, respectively) . There were no differences in MI or HOMA-IR before and after transplantation between these two groups. Conclusion: Improvement of glucose tolerance after renal transplantation in patients diagnosed with IGT before transplantation is related to improvement of insulin secretion. Disclosure M. Kusumi: None. A. Nakamura: Research Support; Kissei Pharmaceutical Co., Ltd., MSD, Nippon Boehringer Ingelheim, Taisho Pharmaceutical Holdings Co., Ltd. H. Nomoto: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL &amp; BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.

1462-P: Effect of Energy Restriction on the Intracellular Metabolism of Rodent Pancreatic ß-Cells In Vitro and Obese Mice

Background: In pancreatic β-cells under diabetic conditions, metabolic stressors cause mitochondrial dysfunction and reduce oxidative phosphorylation, resulting in impaired intracellular metabolism. It has been suggested that aberrant activation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a role in this impairment. However, it is not clear whether the defect in activation of PFKFB3 is reversible. We investigated the effects of energy restriction on PFKFB3 and other metabolic enzymes in pancreatic β-cells. Methods: INS-1 832/13 cells and islets from C57BL/6J mice were cultured in medium containing a low (5.5 mM; low-G) or a high (22 mM: high-G) glucose concentration for 48 hours, or high-G for 24 hours followed by low-G for another 24 hours. The protein expression of glycolysis-related enzymes was measured using western blotting (WB) . Next, 6-week-old ob/+ and ob/ob mice were fed a standard chow diet ad lib or the same diet restricted to 2 g/day for 4 weeks. The body mass, blood glucose concentration, glucose tolerance, and insulin resistance of the mice were compared. The expression of glycolytic enzymes in the pancreatic islets was evaluated using WB and immunohistochemical staining. Results: In both INS-1 832/13 cells and isolated islets, higher expression of PKFFB3 was observed in the high-G group than in the low-G group. However, this was normalized by changing from a high-G to a low-G environment. Ad lib-fed ob/ob mice showed hyperglycemia and greater weight gain than ob/+ mice. The expression of PFKFB3, isocitrate dehydrogenase, and hexokinase was higher in ad lib-fed ob/ob mice. Restricted feeding suppressed weight gain and improved glucose tolerance versus ad lib-fed ob/ob mice. The high expression of PFKFB3 was ameliorated by restricted feeding. Conclusion: The intracellular metabolic changes in pancreatic β cells that are associated with obesity and diabetes are flexible. Disclosure K. Chiba: Research Support; Grant for Young Researcher from Japan Association for Diabetes Education and Care, Japan Diabetes Society Junior Scientist Development Grant, Japan Society for the Promotion of Science, MSD Life Science Foundation, Promotion for Young Research Talent and Network, The Akiyama Life Science Foundation, The Uehara Memorial Foundation. H. Nomoto: None. R. Izumihara: None. H. Kameda: None. K. Cho: None. H. Miyoshi: Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Kowa Company, Ltd., LifeScan, Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. Speaker's Bureau; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kowa Company, Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd. T. Atsumi: Consultant; AbbVie Inc., AstraZeneca, MEDICAL &amp; BIOLOGICAL LABORATORIES CO., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Inc. Research Support; AbbVie Inc., Alexion Pharmaceuticals, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; AbbVie Inc., Astellas Pharma Inc., Bristol-Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eisai Co., Ltd., Eli Lilly and Company, Kyowa Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Pfizer Inc., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Limited, UCB, Inc.