Non-severe hypoglycemia in type 1 diabetes: a randomized crossover trial comparing two quantities of oral carbohydrates at different insulin-induced hypoglycemia ranges.

Aims: Non-severe hypoglycemia (NS-H) is challenging for people living with type 1 diabetes (PWT1D) and often results from relative iatrogenic hyper-insulinemia. Current guidelines recommend a one-size-fits-all approach of 15-20 g of simple carbohydrates (CHO) every 15 min regardless of the triggering conditions of the NS-H event. We aimed to test different amounts of CHO to treat insulin-induced NS-H at various glucose ranges. Methods: This is a randomized, four-way, crossover study involving PWT1D, testing NS-H treatment outcomes with 16 g vs. 32 g CHO at two plasma glucose (PG) ranges: A: 3.0-3.5 mmol/L and B: <3.0 mmol/L. Across all study arms, participants consumed an additional 16 g of CHO if PG was still <3.0 mmol/L at 15 min and <4.0 mmol/L at 45 min post-initial treatment. Subcutaneous insulin was used in a fasting state to induce NS-H. Participants had frequent venous sampling of PG, insulin, and glucagon levels. Results: Participants (n = 32; 56% female participants) had a mean (SD) age of 46.1 (17.1) years, had HbA1c at 54.0 (6.8 mmol/mol) [7.1% (0.9%)], and had a diabetes duration of 27.5 (17.0) years; 56% were insulin pump users. We compared NS-H correction parameters between 16 g and 32 g of CHO for range A, 3.0-3.5 mmol/L (n = 32), and range B, <3.0 mmol/L (n = 29). Change in PG at 15 min for A: 0.1 (0.8) mmol/L vs. 0.6 (0.9) mmol/L, p = 0.02; and for B: 0.8 (0.9) mmol/L vs. 0.8 (1.0) mmol/L, p = 1.0. Percentage of participants with corrected episodes at 15 min: (A) 19% vs. 47%, p = 0.09; (B) 21% vs. 24%, p = 1.0. A second treatment was necessary in (A) 50% vs. 15% of participants, p = 0.001; (B) 45% vs. 34% of participants, p = 0.37. No statistically significant differences in insulin and glucagon parameters were observed. Conclusions: NS-H, in the context of hyper-insulinemia, is difficult to treat in PWT1D. Initial consumption of 32 g of CHO revealed some advantages at the 3.0-3.5 mmol/L range. This was not reproduced at lower PG ranges since participants needed additional CHO regardless of the amount of initial consumption. Clinical trial registration: ClinicalTrials.gov, identifier NCT03489967.

A glycosylated hemoglobin A1c above 6% (42 mmol/mol) is associated with a high risk of developing Cystic Fibrosis-Related Diabetes and a lower probability of weight gain in both adults and children with Cystic Fibrosis.

OBJECTIVES: The classical glycosylated hemoglobin A1c threshold of 6.5% is an insensitive screening test for cystic fibrosis-related diabetes (CFRD). We sought to identify CF-specific A1C thresholds associated with 1) risk of progression to CFRD and 2) changes in body mass index (BMI) and forced expiratory volume (FEV1). METHODS: We studied the cross sectional and longitudinal associations between A1c, BMI, and FEV1 in 2 cohorts of 223 children (followed for up to 8 years) and 289 adults (followed for a mean of 7.5 ± 4.3 years) with CF but without diabetes at baseline and undergoing regular assessments including Oral Glucose Tolerance Test (OGTT). RESULTS: For the onset of OGTT-defined CFRD optimal A1c threshold was 5.9% in adults (sensitivity: 67% and specificity: 71%) and 5.7% for children (sensitivity: 60% and specificity: 47%). Kaplan-Meier analysis of progression to CFRD according to baseline A1C showed increased the risk of developing CFRD for A1c ≥ 6.0% in adults (P = 0.002) and ≥ 5.5% in children (p = 0.012). Temporal changes in BMI and FEV1 according to baseline A1C in adults were assessed with a linear mixed-effect model, BMI significantly increased over time in subjects with a baseline A1c < 6%, but those with a A1C ≥ 6.0% gained significantly less weight over time (P = 0.05). There was no difference in FEV1 according to baseline A1c category. CONCLUSION: An A1C above 6% may be associated with a high risk of developing CFRD and a lower probability of weight gain in both adults and children with CF.

Time in Therapeutic Range With Vitamin K Antagonists in Congenital Heart Disease: A Multicentre Study.

BACKGROUND: Vitamin K antagonists (VKAs) are frequently prescribed to patients with congenital heart disease (CHD) for atrial arrhythmias or Fontan palliation, but there is a paucity of data regarding time spent in the therapeutic range (TTR). We sought to determine the TTR in patients with CHD and atrial arrhythmias or Fontan palliation prescribed VKAs and explore associations with thromboembolic and bleeding events. METHODS: A multicentre North American cohort study was conducted on patients with CHD who received VKAs for sustained atrial arrhythmia or Fontan palliation. TTR was calculated using the Rosendaal linear interpolation method. Generalized estimating equations were used to explore factors associated with time outside the therapeutic range. RESULTS: A total of 567 patients, aged 33 ± 17 years, 56% female, received VKAs for 11.5 ± 8.4 years for atrial arrhythmias (63.0%) or Fontan palliation (58.0%). CHD was simple, moderate, and complex in 10.8%, 20.3%, and 69.0%, respectively. Site investigators perceived good control over international normalized ratio (INR) levels in most patients (75.3%), with no or minor compliance or adherence issues (85.6%). The mean TTR was 41.9% (95% confidence interval [CI], 39.0%-44.8%). Forty-seven (8.3%) and 34 (6.0%) patients had thromboembolic and bleeding events, respectively. Thromboembolic events were associated with a higher proportion of time below the therapeutic range (31.3% vs 19.1%, P = 0.003) and bleeding complications with a higher proportion of time above the therapeutic range (32.5% vs 19.5%, P = 0.006). CONCLUSIONS: Patients with CHD who receive VKAs spend < 42% of their time with INR levels in the therapeutic range, with repercussions regarding thromboembolic and bleeding complications.

Glycated Hemoglobin as a First-line Screening Test for Cystic Fibrosis‒Related Diabetes and Impaired Glucose Tolerance in Children With Cystic Fibrosis: A Validation Study.

OBJECTIVES: Our aims in this study were to document the screening rate for cystic fibrosis‒related diabetes (CFRD) in children followed at a cystic fibrosis (CF) clinic in Canada and to evaluate the accuracy of various glycated hemoglobin (A1C) cutoffs to screen for CFRD and impaired glucose tolerance (IGT) in a pediatric CF population. METHODS: The CFRD screening rate was calculated over a follow-up period of up to 8 years among children who attended the CF clinic between 1993 and 2018. Test performance of A1C at various thresholds ranging from 5.5% to 6.2% was compared with the oral glucose tolerance test (OGTT) as the reference method. Children with CF aged ≥10 years with an OGTT performed within 120 days of A1C measurement were included in the analysis. RESULTS: The overall CFRD screening rate was 53.0%. A total of 256 children were included for the A1C performance analysis, of whom 8.6% had an OGTT-confirmed CFRD diagnosis. An A1C threshold of 5.8% demonstrated an optimal balance between sensitivity (90.9%) and specificity (60.7%) for CFRD screening, leading to a potential reduction of 56.3% of the annual required OGTTs. A1C demonstrated poor accuracy for identifying children with IGT. CONCLUSIONS: An A1C threshold ≥5.8% allows for identification of children requiring further CFRD investigations, which may reduce the clinical burden of children with CF without compromising the ability of early CFRD diagnosis.

Comparison of two carbohydrate intake strategies to improve glucose control during exercise in adolescents and adults with type 1 diabetes.

BACKGROUND AND AIMS: During aerobic physical activity (PA), hypoglycemia is common in people with type 1 diabetes (T1D). Few studies have compared the effectiveness of different carbohydrate (CHO) intake strategies to prevent PA-induced hypoglycemia. Our objective was to compare the efficacy of two CHO intake strategies, same total amount but different CHO intake timing, to maintain glucose levels in the target range (4.0-10.0 mmol/L) during PA in people with T1D. METHODS AND RESULTS: An open-label, randomized, crossover study in 33 participants (21 adults; 12 adolescents). Participants practiced 60 min PA sessions (ergocyle) at 60% VO2peak 3.5 h after lunch comparing an intake of 0.5 g of CHO per kg of body weight applied in a pre-PA single CHO intake (SCI) or in a distributed CHO intake (DCI) before and during PA. The percentage of time spent in glucose level target range during PA was not different between the two strategies (SCI: 75 ± 35%; DCI: 87 ± 26%; P = 0.12). Hypoglycemia (<4.0 mmol/L) occurred in 4 participants (12%) with SCI compared to 6 participants (18%) with DCI (P = 0.42). The SCI strategy led to a higher increase (P = 0.01) and variability of glucose levels (P = 0.04) compared with DCI. CONCLUSIONS: In people living with T1D, for a 60 min moderate aerobic PA in the post-absorptive condition, a 0.5 g/kg CHO intake helped most participants maintain acceptable glycemic control with both strategies. No clinically significant difference was observed between the SCI and DCI strategies. ClinicalTrials.gov Identifier: NCT03214107 (July 11, 2017).

Influence of pre-diabetic and pancreatic exocrine states on pulmonary and nutritional status in adults with Cystic Fibrosis.

BACKGROUND: In 1992, a landmark study demonstrated clinical deterioration in respiratory function and nutritional status prior to the onset of cystic fibrosis-related diabetes (CFRD). We re-evaluated this outcome. METHODS: The Montreal Cystic Fibrosis Cohort is a prospective CFRD screening study. We performed a 6-year retrospective analysis of nutritional parameters and FEV1 (%) in subjects who developed incident CFRD and in controls who maintained normoglycemia (NG). In the former group, data was collected over 6 years prior to diabetes onset. RESULTS: Subjects (n = 86) had a mean age of 31.7 ± 8.1 years, BMI of 23.0 ± 4.0 kg/m2, and FEV1% of 70.1 ± 24.2%. Eighty-one percent had pancreatic insufficiency (PI). Patients were grouped as follows: NG+PS (pancreatic sufficient) (n = 16), NG+PI (pancreatic insufficient) (n = 21), CFRD+PS (n = 3) and CFRD+PI (n = 46). At their most recent screen NG+PS subjects had significantly greater BMI, as compared to NG+PI and CFRD+PI groups (26.2 ± 3.6 kg/m2 vs 22.6 ± 4.2 kg/m2 vs 22.1 ± 3.5 kg/m2, p = 0.0016). FEV1 was significantly greater in the NG+PS group (91.5 ± 16.8% vs 67.8 ± 25.3% vs 63.5 ± 22.2%, p = 0.0002). The rates of change in weight, BMI, fat mass (%), and FEV1 prior to the most recent visit (NG+PS, NG+PI groups) or to the diagnosis of de novo CFRD were similar between groups. CONCLUSION: In a contemporary context, CFRD onset is not preceded by deterioration in BMI, fat mass, or pulmonary function. Low BMI and FEV1 are more closely associated with PI than a pre-diabetic state.

Atrial arrhythmias and patient-reported outcomes in adults with congenital heart disease: An international study.

BACKGROUND: Atrial arrhythmias (ie, intra-atrial reentrant tachycardia and atrial fibrillation) are a leading cause of morbidity and hospitalization in adults with congenital heart disease (CHD). Little is known about their effect on quality of life and other patient-reported outcomes (PROs) in adults with CHD. OBJECTIVE: The purpose of this study was to assess the impact of atrial arrhythmias on PROs in adults with CHD and explore geographic variations. METHODS: Associations between atrial arrhythmias and PROs were assessed in a cross-sectional study of adults with CHD from 15 countries spanning 5 continents. A propensity-based matching weight analysis was performed to compare quality of life, perceived health status, psychological distress, sense of coherence, and illness perception in patients with and those without atrial arrhythmias. RESULTS: A total of 4028 adults with CHD were enrolled, 707 (17.6%) of whom had atrial arrhythmias. After applying matching weights, patients with and those without atrial arrhythmias were comparable with regard to age (mean 40.1 vs 40.2 years), demographic variables (52.5% vs 52.2% women), and complexity of CHD (15.9% simple, 44.8% moderate, and 39.2% complex in both groups). Patients with atrial arrhythmias had significantly worse PRO scores with respect to quality of life, perceived health status, psychological distress (ie, depression), and illness perception. A summary score that combines all PRO measures was significantly lower in patients with atrial arrhythmias (-3.3%; P = .0006). Differences in PROs were consistent across geographic regions. CONCLUSION: Atrial arrhythmias in adults with CHD are associated with an adverse impact on a broad range of PROs consistently across various geographic regions.

A single-blind, randomised, crossover study to reduce hypoglycaemia risk during postprandial exercise with closed-loop insulin delivery in adults with type 1 diabetes: announced (with or without bolus reduction) vs unannounced exercise strategies.

AIMS/HYPOTHESIS: For individuals living with type 1 diabetes, closed-loop insulin delivery improves glycaemic control. Nonetheless, maintenance of glycaemic control during exercise while a prandial insulin bolus remains active is a challenge even to closed-loop systems. We investigated the effect of exercise announcement on the efficacy of a closed-loop system, to reduce hypoglycaemia during postprandial exercise. METHODS: A single-blind randomised, crossover open-label trial was carried out to compare three strategies applied to a closed-loop system at mealtime in preparation for exercise taken 90 min after eating at a research testing centre: (1) announced exercise to the closed-loop system (increases target glucose levels) in addition to a 33% reduction in meal bolus (A-RB); (2) announced exercise to the closed-loop system and a full meal bolus (A-FB); (3) unannounced exercise and a full meal bolus (U-FB). Participants performed 60 min of exercise at 60% [Formula: see text] 90 min after eating breakfast. The investigators were not blinded to the interventions. However, the participants were blinded to the sensor glucose readings and to the insulin infusion rates throughout the intervention visits. RESULTS: The trial was completed by 37 adults with type 1 diabetes, all using insulin pumps: mean±SD, 40.0 ± 15.0 years of age, HbA1c 57.1 ± 10.8 mmol/mol (7.3 ± 1.0%). Reported results were based on plasma glucose values. During exercise and the following 1 h recovery period, time spent in hypoglycaemia (<3.9 mmol/l; primary outcome) was reduced with A-RB (mean ± SD; 2.0 ± 6.2%) and A-FB (7.0 ± 12.6%) vs U-FB (13.0 ± 19.0%; p < 0.0001 and p = 0.005, respectively). During exercise, A-RB had the least drop in plasma glucose levels: A-RB -0.3 ± 2.8 mmol/l, A-FB -2.6 ± 2.9 mmol/l vs U-FB -2.4 ± 2.7 mmol/l (p < 0.0001 and p = 0.5, respectively). Comparison of A-RB vs U-FB revealed a decrease in the time spent in target (3.9-10 mmol/l) by 12.7% (p = 0.05) and an increase in the time spent in hyperglycaemia (>10 mmol/l) by 21% (p = 0.001). No side effects were reported during the applied strategies. CONCLUSIONS/INTERPRETATION: Combining postprandial exercise announcement, which increases closed-loop system glucose target levels, with a 33% meal bolus reduction significantly reduced time spent in hypoglycaemia compared with the other two strategies, yet at the expense of more time spent in hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT0285530 FUNDING: JDRF (2-SRA-2016-210-A-N), the Canadian Institutes of Health Research (354024) and the Fondation J.-A. DeSève chair held by RR-L.

Digoxin, mortality, and cardiac hospitalizations in patients with atrial fibrillation and heart failure with reduced ejection fraction and atrial fibrillation: An AF-CHF analysis.

BACKGROUND: Recent publications have raised serious concerns regarding the safety of digoxin for atrial fibrillation (AF). However, the subgroup of patients with reduced ejection fraction and AF have been speculated to derive clinical benefit from digoxin. We aimed to assess the impact of digoxin on mortality and cardiovascular hospitalizations in the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial since all AF-CHF patients had an ejection fraction ≤35% and AF. METHODS AND RESULTS: Using marginal structural modeling, a contemporary statistical method that overcomes limitations of traditional modeling techniques and reduces bias, we assessed the impact of digoxin on the pre-specified primary and secondary outcomes of the AF-CHF trial, i.e., all-cause, cardiac and arrhythmic death as well as cardiovascular hospitalization. Among 1376 patients, 869 (65%) were on digoxin at one-year follow-up. Over a mean (SD) follow-up of 37 (19) months (maximum 74 months), 445 (32%) patients died, 357 (26%) from cardiovascular causes and 159 (12%) from arrhythmic death. Digoxin was significantly associated with all-cause, cardiac, and arrhythmic death, with estimated hazard ratios (HR) of 1.39 (95% confidence interval [CI] 1.11-1.73, P = 0.004), 1.44 (95% CI 1.13-1.82, P = 0.003), and 2.03 (95% CI 1.63-2.54, P < 0.0001), respectively. Digoxin was not associated with cardiovascular hospitalizations [HR 1.12 (95% CI 0.91-1.37), P = 0.29]. CONCLUSION: Digoxin is associated with increased all-cause mortality among patients with combined heart failure with reduced ejection fraction and AF, which is predominantly driven by arrhythmic deaths. In contrast, cardiovascular hospitalizations were not impacted by digoxin.

Learning through observing: Effects of modeling truth- and lie-telling on children's honesty.

The current study examined the influence of observing another's lie- or truth-telling - and its consequences - on children's own honesty about a transgression. Children (N = 224, 5-8 years of age) observed an experimenter (E) tell the truth or lie about a minor transgression in one of five conditions: (a) Truth-Positive Outcome - E told the truth with a positive outcome; (b) Truth-Negative Outcome - E told the truth with a negative outcome; (c) Lie-Positive Outcome - E lied with a positive outcome; (d) Lie-Negative Outcome - E lied with a negative outcome; (e) Control - E did not tell a lie or tell the truth. Later, to examine children's truth- or lie-telling behavior, children participated in a temptation resistance paradigm where they were told not to peek at a trivia question answer. They either peeked or not, and subsequently lied or told the truth about that behavior. Additionally, children were asked to give moral evaluations of different truth- and lie-telling vignettes. Overall, 85% of children lied. Children were less likely to lie about their own transgression in the TRP when they had previously witnessed the experimenter tell the truth with a positive outcome or tell a lie with a negative outcome.

Implantable cardioverter-defibrillators and patient-reported outcomes in adults with congenital heart disease: An international study.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are increasingly being used to prevent sudden death in the growing population of adults with congenital heart disease (CHD). However, little is known about their impact on patient-reported outcomes (PROs). OBJECTIVE: The purpose of this study was to assess and compare PROs in adults with CHD with and without ICDs. METHODS: A propensity-based matching weight analysis was conducted to evaluate PROs in an international cross-sectional study of adults with CHD from 15 countries across 5 continents. RESULTS: A total of 3188 patients were included: 107 with ICDs and 3081 weight-matched controls without ICDs. ICD recipients were an average age of 40.1 ± 12.4 years, and >95% had moderate or complex CHD. Defibrillators were implanted for primary and secondary prevention in 38.3% and 61.7%, respectively. Perceived health status, psychological distress, sense of coherence, and health behaviors did not differ significantly among patients with and without ICDs. However, ICD recipients had a more threatening view of their illness (relative % difference 8.56; P = .011). Those with secondary compared to primary prevention indications had a significantly lower quality-of-life score (Linear Analogue Scale 72.0 ± 23.1 vs 79.2 ± 13.0; P = .047). Marked geographic variations were observed. Overall sense of well-being, assessed by a summary score that combines various PROs, was significantly lower in ICD recipients (vs controls) from Switzerland, Argentina, Taiwan, and the United States. CONCLUSION: In an international cohort of adults with CHD, ICDs were associated with a more threatening illness perception, with a lower quality of life in those with secondary compared to primary prevention indications. However, marked geographic variability in PROs was observed.

Long-Term Benefits of Rapid Antiretroviral Therapy Initiation in Reducing Medical and Overall Health Care Costs Among Medicaid-Covered Patients with Human Immunodeficiency Virus.

BACKGROUND: New guidelines for the treatment of human immunodeficiency virus (HIV) suggest that morbidity and mortality could be reduced if antiretroviral therapy (ART) was initiated immediately after diagnosis, regardless of CD4 cell count. OBJECTIVE: To assess real-world time to ART initiation and describe medical, pharmacy, and total health care costs in the 6-, 12-, 24-, and 36-month periods after HIV diagnosis based on time to ART initiation among Medicaid-covered patients. METHODS: Multistate Medicaid data (January 2012-March 2017) was used to identify adults with HIV-1 initiating ART ≤ 360 days of initial HIV-1 diagnosis. People living with HIV (PLWH) were sorted into mutually exclusive cohorts based on time from diagnosis to ART initiation (≤ 14 days, > 14 to ≤ 60 days, > 60 to ≤ 180 days, and > 180 to ≤ 360 days). ART regimen had to include a protease inhibitor, an integrase strand transfer inhibitor, or a non-nucleoside reverse transcriptase inhibitor, with ≥ 2 nucleoside reverse transcriptase inhibitors. Medical, pharmacy, and total health care costs in the 6, 12, 24, and 36 months following HIV diagnosis were stratified by timeliness of ART initiation. RESULTS: Of 974 patients, 347 (35.6%) initiated ART > 360 days after diagnosis and were excluded. Among the remaining 627 eligible patients, mean age was 39.9 years, 42.7% were female, and 53.9% were black. Among them, 128 (20.4%) were treated ≤ 14 days, 228 (36.4%) between > 14 and ≤ 60 days, 163 (26.0%) between > 60 and ≤ 180 days, and 108 (17.2%) between > 180 and ≤ 360 days. Among patients treated ≤ 180 days, 4.6% had ≥ 1 opportunistic infection in the 6-month period before ART initiation; this proportion reached 5.6% for patients treated >180 and ≤ 360 days. Over the 6-, 12-, 24-, and 36-month periods after diagnosis, per-patient-per-month (PPPM) medical costs were lower for patients who initiated ART ≤ 14 days than for those who initiated > 180 and ≤ 360 days after diagnosis (6 months: $1,611 [≤ 14 days] vs. $3,008 [> 180 and ≤ 360 days]; 12 months: $1,188 vs. $2,110; 24 months: $754 vs. $1,368; 36 months: $651 vs. $1,196). Over the same periods, medical costs generally accounted for > 50% of total health care costs for patients who initiated ART between > 60 and ≤ 180 days and > 180 and ≤ 360 days and for 30%-40% of total health care costs for patients treated ≤ 14 days and between > 14 and ≤ 60 days. Total PPPM health care costs increased with delay of ART initiation in the 36-month period after diagnosis ($2,058 [treated ≤ 14 days] vs. $2,310 [treated between > 180 and ≤ 360 days]). CONCLUSIONS: In this study from 2012 to 2017 of Medicaid PLWH treated with ART, 20.4% initiated ART ≤14 days of HIV diagnosis. Patients with delayed ART initiation accumulated more total health care costs in the 36-month period after HIV diagnosis than those initiated within 14 days, highlighting the long-term benefit of rapid ART initiation. An important opportunity remains to engage PLWH in care more rapidly. DISCLOSURES: This study was supported by Janssen Scientific Affairs, which was involved in the study design, interpretation of results, manuscript preparation, and publication decisions. Emond, Romdhani, Lefebvre, and Côté-Sergent are employees of Analysis Group, a consulting company that was contracted by Janssen Scientific Affairs to conduct this study and develop the manuscript. Shohoudi was an employee of Analysis Group at the time the study was conducted. Benson, Tandon, Chow, and Dunn are employees and stockholders of Johnson & Johnson. Parts of the material in this study have been presented at the HIV Drug Therapy Meeting; October 28-31, 2018; Glasgow, UK, and the AMCP Annual Meeting; March 25-28, 2019; San Diego, CA.

Thromboembolic Risk After Atriopulmonary, Lateral Tunnel, and Extracardiac Conduit Fontan Surgery.

BACKGROUND: Thromboembolic events contribute greatly to morbidity and mortality following Fontan surgery for univentricular hearts. OBJECTIVES: This study sought to evaluate the effect of type of Fontan surgery on thromboembolic risk. METHODS: A North American multicenter retrospective cohort study enrolled 522 patients with Fontan palliation consisting of an atriopulmonary connection (APC) (21.4%), lateral tunnel (LT) (41.8%), or extracardiac conduit (EC) (36.8%). Thromboembolic complications and new-onset atrial arrhythmia were reviewed and classified by a blinded adjudicating committee. Thromboembolic risk across surgical techniques was assessed by multivariable competing-risk survival regression. RESULTS: Over a median follow-up of 11.6 years, 10- and 20-year freedom from Fontan conversion, transplantation, or death was 94.7% and 78.9%, respectively. New-onset atrial arrhythmias occurred in 4.4, 1.2, and 1.0 cases per 100 person-years with APC, LT, and EC, respectively. APC was associated with a 2.82-fold higher risk of developing atrial arrhythmias (p < 0.001), with no difference between LT and EC (p = 0.95). A total of 71 thromboembolic events, 32 systemic and 39 venous, occurred in 12.8% of subjects, for an overall incidence of 1.1%/year. In multivariable analyses, EC was independently associated with a lower risk of systemic (hazard ratio [HR]: 0.20 vs. LT; 95% confidence interval [CI]: 0.04 to 0.97) and combined (HR: 0.34 vs. LT; 95% CI: 0.13 to 0.91) thromboembolic events. A lower incidence of combined thromboembolic events was also observed with antiplatelet agents (HR: 0.54; 95% CI: 0.32 to 0.92) but not anticoagulation (p = 0.53). CONCLUSIONS: The EC Fontan was independently associated with a lower thromboembolic risk after controlling for time-varying effects of atrial arrhythmias and thromboprophylaxis.

Variability in the Echocardiographic Evaluation of the Systemic Right Ventricle.

BACKGROUND: Echocardiographic evaluation of the systemic right ventricle (sRV) remains challenging in patients with transposition of the great arteries (TGA) corrected by an atrial switch (AS) and with congenitally corrected TGA (ccTGA). The aim of this study was to determine the interobserver and intraobserver variability of echocardiographic parameters for sRV size and systolic function. METHODS: Six independent observers retrospectively interpreted 44 previously acquired echocardiograms (25 patients with TGA/AS and 19 patients with ccTGA). Quantitative parameters included inlet and longitudinal diameters, systolic and diastolic areas, fractional area change (FAC), and wall thickness. sRV dilatation and systolic function were qualitatively graded as normal, mild, moderate, or severe. sRV hypertrophy was graded as present or absent. Intraclass correlation coefficients (ICCs) and Kappa statistics were computed to assess interobserver variability. Images from 10 patients (5 TGA/AS and 5 ccTGA) were reinterpreted at a 1-month interval, and ICC and Kendall tau b statistics were computed to assess intraobserver variability. RESULTS: Interobserver and intraobserver agreement were good to excellent for sRV diameters, areas and FAC (ICC, 0.49-0.97), except for the sRV wall thickness (ICC < 0) and the FAC for 1 observer. Interobserver agreement was poor for the qualitative assessment of sRV size and systolic function (Kappa < 0.25), but with a good to excellent intraobserver agreement. CONCLUSIONS: These findings suggest that overall appreciation of sRV size and systolic function relies on variable interpretation of measurements by observers. Readers experienced in CHD and with clear thresholds for quantitative parameters, along with a validated algorithm, are required to guide the evaluation of sRV.

Use of digoxin in atrial fibrillation: One step further in the mortality controversy from the AFFIRM study.

BACKGROUND: Whether there is a causal association between digoxin and mortality among patients with atrial fibrillation (AF), with or without congestive heart failure (HF), has been controversial; in particular, two prior analyses of data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial have yielded conflicting results. We sought to investigate how digoxin impacts mortality, in the full AFFIRM cohort and for various subgroups, by applying marginal structural modeling (MSM) to AFFIRM data. METHODS: MSM is a newer statistical approach, which estimates causal association in the absence of randomization. MSM more effectively accounts for time-varying treatment and mitigates potential biases, in contrast to the two statistical approaches used in prior analyses of the AFFIRM data. RESULTS: Among 4,060 patients in AFFIRM, 660 (16.3%) died during follow-up. Digoxin was associated with significantly higher mortality in the full cohort (estimated hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.11-1.60, P  =  0.002) and in 3,121 patients without HF (HR 1.36, 95% CI 1.07-1.72, P  =  0.011). There was a trend toward higher mortality with digoxin in 939 patients with HF (HR 1.29, 95% CI 0.96-1.72, P  =  0.090). Associations were nonsignificant in 463 patients with HF and left ventricular ejection fraction (EF) ≥40% and in 155 patients with EF ≤30%. CONCLUSIONS: Digoxin is associated with significantly increased mortality among AFFIRM patients collectively, as determined by MSM statistical methodology. However, the impact of digoxin among AFFIRM patients with coexisting HF is inconclusive.

Transvenous Lead Extraction in Adults With Congenital Heart Disease: Insights From a 20-Year Single-Center Experience.

BACKGROUND: Safety and feasibility data on transvenous lead extraction (TLE) in the challenging population of adults with congenital heart disease (A-CHD) are limited. Herein, we report the results of TLE in A-CHD during a 20-year period. METHODS AND RESULTS: All consecutive TLE procedures in A-CHD were included in a monocentric prospective registry from 1996. A total of 121 leads were extracted in 49 A-CHD (median age, 38 years; 51% men) during 71 TLE procedures. Twenty-four (49%) patients had transposition of the great arteries. Main indications for extraction were infection in 34 (48%) and lead failure in 22 (31%). A laser sheath was required for 56 (46%) leads and a femoral approach for 10 (8%). Complete TLE was achieved for 111 leads (92%). In multivariable analysis, lead duration (odds ratio, 1.02; 95% confidence interval, 1.00-1.04; P<0.01) and number of previous cardiac surgeries (odds ratio, 2.65; 95% confidence interval, 1.52-4.67; P<0.01) were predictive of TLE failure. No perioperative death or pericardial effusion was observed. Subpulmonary atrioventricular valve regurgitation increased in 8 patients (5 with transposition of the great arteries) and was independently associated with an implantable cardioverter defibrillator lead (odds ratio, 9.69; 95% confidence interval, 1.31-71.64; P=0.03) and valvular vegetation (odds ratio, 7.29; 95% confidence interval, 1.32-40.51; P=0.02). After a median of 54 (19-134) months of follow-up after the first TLE, 3 deaths occurred independently from lead management. CONCLUSIONS: Despite complex anatomic issues, TLE can be achieved successfully in most A-CHD using advanced extraction techniques. Subpulmonary atrioventricular valve regurgitation is a prevalent complication, particularly in patients with transposition of the great arteries.

Bayesian adaptive trials for rare cardiovascular conditions.

Escalating costs of cardiovascular trials are limiting medical innovations, prompting the development of more efficient and flexible study designs. The Bayesian paradigm offers a framework conducive to adaptive trial methodologies and is well suited for the study of small populations. Bayesian adaptive trials provide a statistical structure for combining prior information with accumulating data to compute probabilities of unknown quantities of interest. Adaptive design features are useful in modifying randomization schemes, adjusting sample sizes and providing continuous surveillance to guide decisions on dropping study arms or premature trial interruption. Advantages include greater efficiency, minimization of risks, inclusion of knowledge as it is generated, cost savings and more intuitive interpretability. Extensive high-level computations are facilitated by an expanding armamentarium of available tools.

Reducing radiation exposure during procedures performed in the electrophysiology laboratory.

INTRODUCTION: Expert societies recently published strong recommendations to reduce the exposure of patients and staff to ionizing radiation (IR) during interventional and electrophysiology (EP) procedures. However, adherence to these guidelines remains difficult and the impact of implementing such recommendations is poorly characterized. METHODS AND RESULTS: We conducted a single-center cohort study to quantify radiation exposure over time in three EP laboratories at the Montreal Heart Institute during 5,546 consecutive procedures from 2012 to 2015 by 11 primary operators. Overall, 2,618 (47.2%) procedures were catheter-based and 2,928 (52.8%) were device interventions. Interventions to reduce radiation exposure included educational initiatives to raise awareness (i.e., limiting cine acquisition, patient position, table height), slower frame rate, lower radiation dose per pulse, collimation, and integration with 3-D mapping systems and/or MediGuide technology. An 85% reduction in IR exposure was observed from 2012 to 2015, with the mean dose-area-product (DAP) decreasing from 7.65 ± 0.05 Gy·cm2 to 1.15 ± 0.04 Gy·cm2 (P < 0.001). This was true for catheter-based procedures (mean DAP 16.99 ± 0.08 to 2.00 ± 0.06 Gy·cm2 , P < 0.001) and device interventions (mean DAP 4.18 ± 0.06 to 0.64 ± 0.05 Gy·cm2 , P < 0.001). The median effective dose of IR recorded per quarter by 282 cervical dosimeters on EP staff decreased from 0.57 (IQR 0.18, 1.03) mSv in 2012 to 0.00 (IQR 0.00, 0.19) mSv in 2015, P < 0.001. CONCLUSION: Enforcing good clinical practices with simple measures and low-dose fluoroscopy settings are highly effective in reducing IR exposure in the EP lab. These promising results should encourage other EP labs to adopt similar protective measures.

Late Onset Postcapillary Pulmonary Hypertension in Patients With Transposition of the Great Arteries and Mustard or Senning Baffles.

BACKGROUND: There is a paucity of data regarding late-onset pulmonary hypertension (PH) in patients with transposition of the great arteries and atrial switch surgery. METHODS AND RESULTS: A retrospective cohort study was conducted on 140 adults with transposition of the great arteries and atrial switch surgery, age 37.3±7.8, 37.1% female, in order to assess the prevalence and characteristics of late-onset PH and explore associated factors. Patients were followed for a median of 32.3 years after atrial switch surgery and 10.0 years after their first referral visit. PH was detected in 18 of 33 (54.5%) patients who had invasive hemodynamic studies. Average age at diagnosis of PH was 33.9±8.1 years. PH was postcapillary in all, with a mean pulmonary artery pressure of 36±12 mm Hg and mean pulmonary capillary wedge pressure of 28±8 mm Hg. PH was diagnosed in 13 of 17 (76.5%) patients who had cardiac catheterization for heart failure or decreased exercise tolerance. In multivariable analyses, systemic hypertension (odds ratio 9.4, 95% confidence interval 2.2-39.4, P=0.002) and heart failure or New York Heart Association class III or IV symptoms (odds ratio 49.8, 95% confidence interval 8.6-289.0, P<0.001) were independently associated with PH. Patients with PH were more likely to develop cardiovascular comorbidities including atrial (P=0.001) and ventricular (P=0.008) arrhythmias, require hospitalizations for heart failure (P<0.001), and undergo tricuspid valve surgery (P<0.001). Mortality was significantly higher in patients with PH (hazard ratio 9.4, 95% confidence interval 2.1-43.0], P<0.001). CONCLUSIONS: Late-onset postcapillary PH is highly prevalent in adults with transposition of the great arteries and atrial switch surgery and is associated with an adverse prognosis.