Long-term Registry Research Articles

In-hospital and 12-month follow-up outcome from the ESC-EORP EHRA Atrial Fibrillation Ablation Long-Term registry: sex differences.

The purpose of this study was to compare sex differences of atrial fibrillation (AF) catheter ablation (CA) and to analyse the opportunities for improved outcomes. All data were collected from the Atrial Fibrillation Ablation Long-Term registry, a prospective, multinational study conducted by the ESC-EORP European Heart Rhythm Association (EHRA) under the EURObservational Research Programme (ESC-EORP). A total of 104 centres in 27 European countries participated. Of 3593 included patients, 1146 (31.9%) were female. Female patients were older (61.0 vs. 56.4 years; P < 0.001), had more comorbidities (hypertension, diabetes, and obesity), more episodes of arrhythmias per month (6.9 vs. 6.2; P < 0.001), and a higher average EHRA score (2.6 vs. 2.4; P < 0.001). The duration of the procedure was shorter in females (160.1 min vs. 167.9 min; P < 0.001), irrespective of additional ablation lesions added to pulmonary vein isolation. Overall cardiovascular complications were more frequent in women than in men (5.7% vs. 3.4%; P < 0.001). Furthermore, cardiac perforations (3.8% vs. 1.3%; P = 0.011) and neurological complications (2.2% vs. 0.3%; P = 0.004) were found in females in less experienced centres than in experienced ones. On a final note, at 12 months, AF recurrence rate was similar in females and males (34.4% vs. 34.2%; P = 0.897), but more females were still on antiarrhythmic drugs (50.6% vs. 44.1%; P < 0.001) when compared with men. Females underwent CA procedures for AF less frequently than males throughout Europe, despite more recurrent symptoms. With the same success rate, severe acute complications remained considerable in females, especially in less experienced centres.

Impact of monitoring on detection of arrhythmia recurrences in the ESC-EHRA EORP atrial fibrillation ablation long-term registry.

Monitoring of patients after ablation had wide variations in the ESC-EHRA atrial fibrillation ablation long-term (AFA-LT) registry. We aimed to compare four different monitoring strategies after catheter AF ablation. The ESC-EHRA AFA-LT registry included 3593 patients who underwent ablation. Arrhythmia monitoring during follow-up was performed by 12-lead electrocardiogram (ECG), Holter ECG, trans-telephonic ECG monitoring (TTMON), or an implanted cardiac monitoring (ICM) system. Patients were selected to a given monitoring group according to the most extensive ECG tool used in each of them. Comparison of the probability of freedom from recurrences was performed by censored log-rank test and presented by Kaplan-Meier curves. The rhythm monitoring methods were used among 2658 patients: ECG (N = 578), Holter ECG (N = 1874), TTMON (N = 101), and ICM (N = 105). A total of 767 of 2658 patients (28.9%) had AF recurrences during follow-up. Censored log-rank test discovered a lower probability of freedom from relapses, which was detected with ICM compared to TTMON, ECG, and Holter ECG (P < 0.001). The rate of freedom from AF recurrences was 50.5% among patients using the ICM while it was 65.4%, 70.6%, and 72.8% using the TTMON, ECG, and Holter ECG, respectively. Comparing all main electrocardiographic monitoring methods in a large patient sample, our results suggest that post-ablation recurrences of AF are significantly underreported by TTMON, ECG, and Holter ECG. The ICM estimates AF ablation recurrences most reliably and should be a preferred mode of monitoring for trials evaluating novel AF ablation techniques.

Spinal Muscular Atrophy: Past, Present, and Future.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletions or mutations in the survival motor neuron (SMN1) gene. SMA is characterized by loss of lower motor neurons (anterior horn cells) in the spinal cord and brainstem nuclei, leading to progressive symmetrical muscle weakness and atrophy. It affects approximately 1 in 6,000 to 1 in 10,000 individuals and is the most common inherited cause of childhood mortality, but this may soon change given recent developments. In December 2016, nusinersen, an antisense oligonucleotide drug, was approved by the United States Food and Drug Administration for the treatment of SMA, and in July 2018, SMA was added to the recommended uniform screening panel, a list of conditions that all states are encouraged to include in their newborn screening (NBS) panels. In this review, we begin with a brief clinical history of the diagnosis of SMA, discuss the current SMA clinical classification system, describe the current treatment, and discuss evolving treatment guidelines. We then discuss the path to include SMA in NBS programs as well as the controversies it engenders because the variability in age at symptom onset means early identification of asymptomatic patients who will not require therapy for years or decades. We also consider alternate population screening opportunities. Next, we consider experimental treatments. We conclude by supporting NBS for SMA with the caveat that a long-term follow-up registry is ethically essential to ensure that the benefits outweigh the harms for all screened infants, including those with milder and/or later-onset forms of SMA.

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Sacubitril/valsartan eligibility and outcomes in the ESC-EORP-HFA Heart Failure Long-Term Registry: bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM-HF trial, ESC guidelines, and real world.

To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacubitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label, the PARADIGM-HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes. Outpatients with HFrEF in the ESC-EORP-HFA Long-Term Heart Failure (HF-LT) Registry between March 2011 and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM-HF and ESC guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM-HF and guideline criteria, respectively. Absent PARADIGM-HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and sub-optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%) and sub-optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility rose from 12% to 28% based on both PARADIGM-HF and guidelines. One-year heart failure hospitalization was higher (12% and 17% vs. 12%) and all-cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared to the enalapril arm of PARADIGM-HF. Among outpatients with HFrEF in the ESC-EORP-HFA HF-LT Registry, 84% met label criteria, while only 12% and 28% met PARADIGM-HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively. Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than the PARADIGM-HF enalapril group.

The impact of left ventricular ejection fraction on heart failure patients with pulmonary hypertension

BackgroundThe most common cause of pulmonary hypertension (PH) in developed countries is left heart disease (LHD, group 2 PH). The development of PH in heart failure (HF) patients is indicative of worse outcomes. ObjectiveThe aim of this study was to evaluate the long term outcomes of HF patients with PH in a national long-term registry. MethodsStudy included 9 cardiology centers across Israel between 01/2013–01/2015, with a 12-month clinical follow-up and 24-month mortality follow-up. Patients were age ≥18 years old with HF and pre-inclusion PH due to left heart disease determined by echocardiography [estimated systolic pulmonary arterial pressure (SPAP) ≥ 50 mmHg]. Patients were categorized into 3 groups: HF with reduced (HFrEF < 40%), mid-range (HFmrEF 40–49%), and preserved (HFpEF ≥ 50%) ejection fraction. ResultsThe registry included 372 patients, with high prevalence of cardiovascular risk factors. Median HF duration was 4 years and 65% were in severe HF New York Heart Association (NYHA) classification ≥3. Mean systolic pulmonary artery pressure (SPAP) was 62 ± 11 mmHg. During 2-years of follow-up, 54 patients (15%) died. Univariable predictors of mortality included NYHA grade 3–4, chronic renal failure, and SPAP ≥ 65 mmHg. Severe PH was associated with mortality in HFpEF, but not HFmrEF or HFrEF, and remained significant after multivariable adjustment with an adjusted hazard ratio of 2.99, (95%CI 1.29–6.91, p = 0.010). ConclusionsThe combination of HFpEF with severe PH was independently associated with increased mortality. Currently, HFpEF patients are included with group 2 PH patients. Defining HFpEF with severe PH as a sub-class may be more appropriate, as these patients are at increased risk and deserve special consideration.

Acute heart failure congestion and perfusion status-impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry.

Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and perfusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and outcomes among congestion/perfusion profiles using this classification. We included 7865 AHF patients classified at admission as: 'dry-warm' (9.9%), 'wet-warm' (69.9%), 'wet-cold' (19.8%) and 'dry-cold' (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management and outcomes. In-hospital mortality was 2.0% in 'dry-warm', 3.8% in 'wet-warm', 9.1% in 'dry-cold' and 12.1% in 'wet-cold' patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: 'wet-warm' vs. 'dry-warm' 1.78 (1.43-2.21) and 'wet-cold' vs. 'wet-warm' 1.33 (1.19-1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: 'wet-warm' vs. 'dry-warm' 1.46 (1.31-1.63) and 'wet-cold' vs. 'wet-warm' 2.20 (1.89-2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher 1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation, diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure during hospitalization were associated with lower risk of residual congestion. Classification based on congestion/perfusion status provides clinically relevant information at hospital admission and discharge. A better understanding of the clinical course of the two entities could play an important role towards the implementation of targeted strategies that may improve outcomes.

PBI23 ANALYSIS OF REIMBURSEMENT STATUS OF 8 APPROVED CELL AND GENE THERAPIES IN THE USA, 6 MAJOR EUROPEAN COUNTRIES, AUSTRALIA, AND JAPAN

A few advanced therapies such as the cell and gene therapies (CGTs) have been approved during the last couple of years. These one shot CGTs are highly priced and lead to challenges for reimbursement. It is the objective of this research to analyse the current process and decisions of the major HTA bodies worldwide and to provide an overview of the status quo. A targeted research for CGTs was conducted (Embase, Medline, and Google Scholar) to identify the regulatory status and the associated indications. At least one market authorization for one indication of gene therapies or CGTs was considered as inclusion criteria for the research. HTA bodies from UK, France, Italy, Spain, Germany, Sweden, Australia, and Japan were used for the global assessment. For the US, ICER reports, and Blue Cross/Blue Shield was used. Four gene therapies (Voretigene neparvovecrzyl, Alipogene tiparvovec, Nusinersen, GSK-2696273) and four CGTs [CAR-T: Tisagenlecleucel, Axicabtagene ciloleucel, Talimogene laherparepvec, TBI-0301 (HSV-Tk)] were identified. The one-time dose cost of these CGTs varies from 373,000US$ (Axicabtagene ciloleucel) to 850,000US$ (Voretigene neparvovecrzyl). For most of the CGTs, the final decision on reimbursement was pending at the time of the analysis. Different models for reimbursement were used such as a money-back guarantee is given by the manufacturer for Strimvelis. However, a major concern for HTA bodies is the lack of evidence on the durability of the therapy in the long-term. Requests for the set-up of long-term registries have also been made (Strimvelis 15 years follow-up). The lack of evidence on long-term efficacy followed by the high price and impact on the budget are the main reasons for not approving reimbursement of the CGTs. Thus, new reimbursement models are necessary for financing these treatments and make them available for the patients and affordable for the health care systems.

SUN-222 Testosterone Treatment in Men with Classical vs. Functional Hypogonadism: A 9-Year Registry

Introduction and Objective Longterm data of Testosterone (T) substitution in hypogonadal men are scarce and clinical value of this treatment is especially debated in men with functional (so called “late-onset”) hypogonadism. A long-term registry comprising various groups of patients provides an efficient tool to approach this issue. Methods Registry data of max. 9 years comprising 650 patients with hypogonadism including 266 men with primary forms (mean age 34.0±11.7 years), 196 with secondary origin (mean age 31.9±12.0 years) and 188 with functional hypogonadism (mean age 42.3±11.3 years) all receiving uniform treatment using intramuscular T undecanoate (1000 mg). Results The registry contained 8358 time points with a subset of metabolic and safety parameters each. Serum T concentrations increased from 5.7±2.3 nmol/L to 19.4±2.8 nmol/L in men with classical hypogonadism and from 7.8±2.4 nmol/L to 19.2±3.1 nmol/L in men with functional hypogonadism (difference in delta T: p<0.0001). There was an initial difference in the distribution of body mass index (BMI): 35.6% of men with classical hypogonadism and 51.6% of men with functional hypogonadism were obese (BMI>30 kg/m2, p=0.0006). Changes over time using Kaplan-Meier models revealed fundamental differences in inter-individual effects: men with functional hypogonadism were more likely to lose 10% weight and 5% of waist circumference (WC) than men with classical hypogonadism (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference for increase in hematocrit. Changes in PSA levels were more likely to occur in functional hypogonadism (hazard ratio 1.3 [1.1-1.6], p=0.003). Significantly more pronounced effects of T substitution in functional hypogonadism could also be attributed to changes in parameters of lipid metabolism (levels of total cholesterol, triglycerides, LDL- and HDL-cholesterol and glucose metabolism). Stepwise multiple Cox regression models could attribute these differences to the initial higher values in BMI, WC, lipids, glucose and age found in functional hypogonadism. The condition as such rather attenuated the effects of testosterone treatment compared to those seen in classical forms of hypogonadism, due to the lower increase of testosterone concentrations during treatment. Conclusions Major new findings regarding effects and safety of T substitution in different groups of hypogonadal men are provided. Effects on factors influencing cardiovascular health are modulated by diagnosis and age. Patients with functional hypogonadism seem to benefit to a larger extent from T substitution, this being a function of their initially worse status in cardiovascular risk factors compared to men with classical forms of hypogonadism.

Not Achieving Sustained Viral Eradication of Hepatitis C Virus After Treatment Leads to Worsening Patient-reported Outcomes.

The causative relationship between the clearance of infections and long-term, health-related quality-of-life (HRQL) improvements in patients with hepatitis C virus (HCV) has been generally accepted. The aim of this study was to assess long-term HRQL trends in HCV patients who did not achieve sustained virologic responses (SVRs) after treatment with direct-acting antivirals. HCV patients who completed treatment in clinical trials and did not achieve SVRs were enrolled in a long-term registry (#NCT01457768). HRQL scores were prospectively collected using the short form-36 instrument (8 HRQL domains and 2 summary scores). There were 242 patients included: they had a median age of 54 years (standard deviation ± 8 years), 85% were male, and 38% had cirrhosis. Before treatment, patients' HRQL scores were similar to the general population norms (all 1-sided P > 0.05), but were followed by significant decreases by the end of treatment (-3.4 to -6.2 points; P < .05 for 5/8 HRQL domains and mental summary). By the time subjects entered the registry, all but 1 of the mean HRQL scores had returned to their pretreatment levels (P > .05). During subsequent periods in the registry, patients experienced further HRQL decrements: up to -9.2 points (P < .05 for all HRQL domains) at Week 24 and up to -8.3 points (P < .05 for 5/8 HRQL domains) at Week 48. Although these HRQL decrements were observed regardless of cirrhosis status, they were more pronounced in patients with cirrhosis (P < .05 for 3/8 HRQL domains). Patients who did not achieve an SVR after treatment experienced worsening HRQL scores in long-term follow-ups. Retreatment of these patients will be important not only to improve their clinical outcomes, but also their quality of life.

Association between antithrombotic treatment and outcomes at 1-year follow-up in patients with atrial fibrillation: the EORP-AF General Long-Term Registry.

In recent years, stroke prevention in patients with atrial fibrillation (AF) has radically changed, with increasing use of non-vitamin K antagonist oral anticoagulants (NOACs). Contemporary European data on AF thromboprophylaxis are needed. We report 1-year follow-up data from the EURObservational Research Programme in Atrial Fibrillation (EORP-AF) General Long-Term Registry. Outcomes were assessed according to antithrombotic therapy. At 1-year follow-up, 9663 (88.0%) patients had available data for analysis: 586 (6.1%) were not treated with any antithrombotic; 681 (7.0%) with antiplatelets only; 4066 (42.1%) with vitamin K antagonist (VKA) only; 3167 (32.8%) with NOACs only; and 1163 (12.0%) with antiplatelet and oral anticoagulant. At 1-year follow-up, there was a low rate of stroke (0.7%) and any thromboembolic event (TE) (1.2%), while haemorrhagic events occurred in 222 patients (2.3%). Cardiovascular (CV) death and all-cause death occurred in 3.9% and 5.2% of patients, respectively. Cumulative survival for all the three main outcomes considered was highest amongst patients treated only with NOACs (P < 0.0001). Multivariable-adjusted Cox regression analysis found that VKA or NOACs use was independently associated with a lower risk for any TE/acute coronary syndrome/CV death, while all treatments were independently associated with a lower risk for CV death and all-cause death. The 1-year follow-up of EORP-AF General Long-Term Registry reported a low occurrence of thromboembolic and haemorrhagic events, although mortality was high. Both VKA and NOACs were associated with a lower risk of all main adverse outcomes. All treatments were associated with a lower risk for CV death and all-cause death.

Socioeconomic Differences in Referral to Phase I Cancer Clinical Trials: A Danish Matched Cancer Case-Control Study.

In this nationwide registry study, we investigated socioeconomic and structural patterns in referral to phase I cancer trials in a case-control study design. Personal identification numbers on all Danish patients referred to the Danish Phase I Unit at Rigshospitalet from 2005 to 2016, and a control group matched on age, sex, type of cancer, year of diagnosis, and time from diagnosis to referral ensured individual-level linkage between several registries. We examined the association between nonclinical factors-indicators of socioeconomic position and distance to the Phase I Unit-and referral using a conditional logistic regression analysis adjusted for several clinical factors. Association between nonclinical factors and enrollment once referred was examined with a Cox proportional hazards regression analysis in an historical cohort study design. Complete data were available for 1,026 (84%) of 1,220 referred patients. Significantly decreased odds for referral were identified for patients with long distance to the Phase I Unit compared with short distance (adjusted odds ratio [OR], 0.35; 95% CI, 0.30 to 0.41), for less education (less than 9 years) compared with more (more than 12 years; OR, 0.69; 95% CI, 0.56 to 0.91), and for belonging to the lowest income quintile compared with the highest (OR, 0.78; 95% CI, 0.62 to 0.97). Medium education (9 to 12 years) compared with more, being outside the workforce compared with being within, and living alone compared with living with a partner were also negatively associated with referral. Among patients referred, 252 enrolled in a trial. Nonclinical factors were not associated with enrollment. On the basis of individual long-term registry data from an unselected cohort, novel anticancer therapies seem to be tested on a socially selected group of patients with cancer.

Analysis of risk factors for antiepileptic drug-induced adverse psychotropic effects in Chinese outpatients with epilepsy

Antiepileptic drugs (AEDs) have adverse psychotropic effects (APEs). To explore the risk factors for AED-induced APEs, we compared Chinese outpatients with epilepsy with and without AED-induced APEs. We reviewed the medical data of outpatients with epilepsy enrolled in the Epilepsy Long-term Follow Up Registry Study (ELFURS) between January 1, 2003 and December 31, 2015. Data on demographics, comorbidities, variables related to epilepsy, AED use, and APEs were collected. APEs were determined by experienced epileptologists based on the definition of “adverse drug reaction (ADR)” proposed by the World Health Organization (WHO) in 1972, and the causality relationship between APEs and suspected medications was assessed based on the WHO-UMC scale. APEs included effects on memory, sleep, behavior, mood, psychotic symptoms, and others in this study. We divided the study population into patients with and without AED-induced APEs and then compared the differences between the two groups using univariate and multivariate methods. A total of 3074 eligible patients were included in this study (1001 patients with AED-induced APEs and 2073 patients without AED-induced APEs). Of all APEs, the effects on memory and sleep were most pronounced. The results show that the female sex (odds ratio [OR] 1.242, 95% confidence interval [CI] 1.055–1.463), psychotic disorder comorbidities (OR 1.815, 95% CI 1.159–2.841), polytherapy with AEDs (OR 1.400, 95% CI 1.061–1.847), and the duration of epilepsy (OR 1.010, 95% CI 1.000–1.020) are significant nondrug risk factors for AED-induced APEs. Recognizing risk factors for APEs may help determine optimal treatment strategies for epilepsy.

Relationship between the CHA2DS2-VASc score and atrial fibrillation in patients hospitalised due to heart failure.

Heart failure (HF) has become an epidemic. A similar situation is also observed for atrial fibrillation (AF). The CHA2DS2-VASc score is one of the most useful tools for thromboembolic risk assessment. The aim of the study was to assess the prevalence of AF in patients with decompensated HF, who were divided into subgroups according to the CHA2DS2-VASc score. We analysed the prevalence of AF in a group of 1108 patients (327 women) hospitalised due to HF decompensa- tion in medical centres of different referral levels. Twenty-one patients refused to participate in the registry. The data were collected from Polish centres included in the European Society of Cardiology Heart Failure Long-Term Registry. The recruit- ment period was from 2011 to 2014. The data were analysed retrospectively. Patients were divided into groups according to the CHA2DS2-VASC score. The study sample was characterised by a high occurrence of AF (44.3%), with the highest prevalence in patients with a CHA2DS2-VASC score ≥ 6 (61.3%, p = 0.01). The CHA2DS2-VASc score may be a useful tool for detecting patients with HF characterised by the highest risk of AF.

Commentary: Cryoballoon vs. radiofrequency ablation for atrial fibrillation-a study of outcome and safety based on the ESC-EHRA atrial fibrillation ablation long-term registry and the Swedish catheter ablation registry.

Commentary: Cryoballoon vs. radiofrequency ablation for atrial fibrillation-a study of outcome and safety based on the ESC-EHRA atrial fibrillation ablation long-term registry and the Swedish catheter ablation registry.

Effect of β-blockers on 1-year survival and hospitalizations in patients with heart failure and atrial fibrillation: results from ESC-HF Pilot and ESC-HF Long-Term Registry.

Introduction The positive effect of β-blocker therapy in patients with heart failure (HF) and atrial fibrillation (AF) has been questioned. Objectives We aimed to assess the effect of β-blockers and heart rate (HR) control on 1-year outcomes in patients with HF and AF. Patients and methods Of the 2019 Polish patients enrolled in ESC-HF Pilot and ESC-HF Long-Term Registry, 797 patients with HF and AF were classified into 2 groups depending on β-blocker use. Additionally, patient survival was compared between 3 groups classified according to HR: lower than 80 bpm, between 80 and 109 bpm, and of 110 bpm or higher. The primary endpoint was all-cause death and the secondary endpoint was all-cause death or HF hospitalization. Results In patients treated with β-blockers, the primary and secondary endpoints were less frequent than in patients not using β-blockers (10.9% vs 25.6%, P = 0.001 and 30.6% vs 44.2%, P = 0.02, respectively). Absence of β-blocker treatment was a predictor of both endpoints in a univariate analysis but remained an independent predictor only of the primary endpoint in a multivariate analysis (hazard ratio for β-blocker use, 0.52; 95% CI, 0.31-0.89; P = 0.02). The primary and secondary endpoints were more frequent in patients with a HR of 110 bpm or higher, but the HR itself did not predict the study endpoints in the univariate analysis. Conclusions β-blocker use might decrease mortality in patients with HF and AF, but it seems to have no impact on the risk of HF hospitalization. An HR of 110 bpm or higher may be related to worse survival in these patients.

PRM21 - MODELLING SURVIVAL OF PATIENTS WITH COMPLETELY RESECTED ADVANCED MELANOMA WITH ADJUVANT TREATMENT OF NIVOLUMAB VERSUS OBSERVATION

Nivolumab demonstrated significant recurrence-free survival (RFS) gains vs. ipilimumab in the phase 3 trial CheckMate-238, whilst the phase 3 trial CA184-029 showed superior RFS gains for ipilimumab vs. placebo. Modelling was used to estimate overall survival (OS) associated with nivolumab compared to observation (no treatment) when OS data was not available in CheckMate-238. Four modelling options were developed using different methods and evidence sources to estimate post-recurrence survival (PRS) and OS. For all options, the RFS parametric survival curves for nivolumab and observation were informed by a patient-level data meta-regression of the two trials. The first option applied a partitioned survival model (PSM), where the parametric OS curve for observation was derived from the CA184-029 placebo arm, and nivolumab OS was based on a surrogacy relationship between RFS and OS specific to adjuvant melanoma. The other options used state-transition Markov models to estimate PRS from different data sources: (1) assumed PRS is identical to OS curves from the PSM, applying a PRS vs OS hazard ratio from CA184-029; (2) used weighted survival of local/regional recurrence data in CA184-029 and a network meta-analysis of advanced melanoma treatments and (3) used PRS from CA184-029. In all options, long-term melanoma registry data were applied to both treatment arms at 10 years. The PSM estimated 21.1 and 13.9 life-years (LYs) for nivolumab and observation, respectively over a life time horizon. Markov option 1 reported 18.5 and 11.1 LYs, option 2 reported 13.9 and 9.1 LYs, and option 3 reported 17.0 and 12.1 LYs for nivolumab and observation, respectively. Modelling can be used to estimate OS for nivolumab and observation. Different modelling methods and evidence sources all predicted superior OS for nivolumab vs. observation, but with varying LY differences. Longer term OS data are required to validate these modelling options.

Internal mammary artery graft failure: Clinical features, management, and long-term outcomes

ObjectiveData on long-term outcomes after internal mammary artery (IMA) coronary graft failure are scarce. Our objective was to describe the clinical characteristics, management, and prognosis after angiographically confirmed IMA graft failure following coronary revascularization. MethodsA three-hospital retrospective registry, observational and descriptive, with prospective follow-up of all consecutive cases of IMA graft failure between 2004 and 2014 was conducted. After treatment, clinical and procedural features were compared between those with and without cardiovascular events. ResultsFifty-seven patients were included (89% male, mean age: 62 years, at surgery) in the registry. Most patients underwent an IMA angioplasty (percutaneous coronary intervention [PCI], 74%). In nine cases, the PCI failed at the graft level, and seven underwent a native vessel revascularization. Native vessel treatment was performed in 20% of the study subjects, all with stents. Finally, medical management was decided in three cases. Events after treatment for IMA graft failure were frequent (50.8%), during a median follow-up of 7.5 years. Acute presentation (hazard ratioMACE = 1.35; 95% confidence interval (CI): 1.12–3.00, p < 0.01), age of the patient (hazard ratioMACE = 1.85, 95% CI: 1.17–2.11, p < 0.01), presence of diabetes mellitus (hazard ratioMACE = 2.75, 95% CI: 1.13–6.69, p = 0.02), and the management modality used (IMA-simple angioplasty VS IMA-stenting: hazard ratioMACE = 5.5, 95% CI: 1.40–21.15, p = 0.01) displayed prognostic relevance on multivariate analysis. All-cause mortality occurred in 21.1% and presentation as infarction (hazard ratioDEATH = 1.05, 95% CI: 1.01–2.17, p = 0.01), age (hazard ratioDEATH = 9.08, 95% CI: 2.52–32.69, p < 0.01), and left ventricular ejection fraction (hazard ratioDEATH = 3.68, 95% CI: 1.65–8.18, p < 0.01) were independent predictors of the same. ConclusionsIn this long-term registry, most patients presented with an acute condition (myocardial infarction, progressive angina) within 12 months after surgery. Acute presentation, age, diabetes mellitus, reduced left ventricular ejection fraction, IMA graft failure segment affected, and the management strategy were related with long-term prognosis.

Left Ventricular Lead Location and Long-Term Outcomes in Cardiac Resynchronization Therapy Patients.

The authors aimed to evaluate the association of left ventricular (LV) lead location and long-term outcomesin MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy). There is limited data on the association of lead location with long-term clinical outcomes in patients with cardiac resynchronization therapy with defibrillator (CRT-D). The LV lead location was classified in 797 patients with CRT-D, in 569 patients with left bundle branch block (LBBB), in 228 patients with non-LBBB, and in 505 patients with an implantable cardioverter-defibrillator (ICD) only. Leads were classified into apical (n= 83) and non-apical (n= 486); with the non-apical LV leads further categorized into anterior (n= 99) and posterior/lateral (n= 387) within LBBB. All-cause mortality and heart failure (HF) events were assessed using Kaplan-Meier and Cox analyses. In CRT-D patients with LBBB and posterior/lateral LV lead location, there was an association with a significant reduction in long-term all-cause mortality (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.37 to 0.79; p=0.001), and HF events (HR: 0.44, 95% CI: 0.33 to 0.60; p< 0.001) compared to an ICD only, accompanied withbetter LV reverse remodeling. CRT-D patients with LBBB and an anterior LV lead location were shown to be associated with a significant reduction in HF events compared to an ICD only (anterior HR: 0.50, 95% CI: 0.30 to 0.82; p= 0.006); however, no association with mortality reduction was observed from CRT-D versus an ICD only. CRT-D wasnot associated with improved outcomes in non-LBBB patients, regardless of LV lead location. In mild HF patients with LBBB and an implanted CRT-D, lateral/posterior, and anterior LV lead locations are similarly associated with reduction in the risk of HF or death events compared to ICD alone. Mortality benefit derived from CRT-D is associated only with patients with lateral/posterior LV lead location. An apical LV lead location should be avoided due to the early risk of death whenever possible. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT], NCT00180271; Multicenter Automatic Defibrillator Implantation Trial WithCardiac Resynchronization Therapy Post Approval Registry [MADIT-CRT-PAR], NCT01294449; and MADIT-CRT Long-Term International Follow-Up Registry - Europe, NCT02060110).

The current state of long-acting growth hormone preparations for growth hormone therapy.

To discuss the rationale of developing long-acting growth hormone (LAGH) preparations, to describe the technologies designed to prolong GH action, and to address key issues regarding efficacy, safety, and monitoring while on treatment. Recombinant human GH is currently approved for daily use and has been shown to restore longitudinal growth, and improve body composition with relatively few side-effects in children and adults with GH deficiency, respectively. However, daily injections can be inconvenient, painful and distressing for some patients, resulting in decreased adherence and efficacy. Over a dozen pharmaceutical companies have designed LAGH preparations that are at various stages of development using a number of different methods to prolong GH action. LAGH will represent an advancement over daily recombinant human GH injections because of fewer injections that may offer increased acceptance, tolerability, and therapeutic flexibility to patients that potentially can improve treatment outcomes. However, given the unphysiological profile of LAGH preparations, long-term surveillance of efficacy and safety are needed. This review summarizes recent developments of LAGH preparations, and highlights the importance of long-term surveillance registries to assess for efficacy and safety that will be essential for understanding the impact of prolonged exposure to these compounds.