Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. METHODS: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. FINDINGS: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). INTERPRETATION: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available. FUNDING: Novo Nordisk.

The Effect of Semaglutide on Mortality and COVID-19-Related Deaths: An Analysis From the SELECT Trial.

BACKGROUND: Patients with overweight and obesity are at increased risk of death from multiple causes, including cardiovascular (CV) death, with few therapies proven to reduce the risk. OBJECTIVES: This study sought to assess the effect of semaglutide 2.4 mg on all-cause death, CV death, and non-CV death, including subcategories of death and death from coronavirus disease-2019 (COVID-19). METHODS: The SELECT (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity) trial randomized 17,604 participants ≥45 years of age with a body mass index ≥27 kg/m2 with established CV disease but without diabetes to once-weekly subcutaneous semaglutide 2.4 mg or placebo; the mean trial duration was 3.3 years. Adjudicated causes of all deaths, COVID-19 cases, and associated deaths were captured prospectively. RESULTS: Of 833 deaths, 485 (58%) were CV deaths, and 348 (42%) were non-CV deaths. Participants assigned to semaglutide vs placebo had lower rates of all-cause death (HR: 0.81; 95% CI: 0.71-0.93), CV death (HR: 0.85; 95% CI: 0.71-1.01), and non-CV death (HR: 0.77; 95% CI: 0.62-0.95). The most common causes of CV death with semaglutide vs placebo were sudden cardiac death (98 vs 109; HR: 0.89; 95% CI: 0.68-1.17) and undetermined death (77 vs 90; HR: 0.85; 95% CI: 0.63-1.15). Infection was the most common cause of non-CV death and occurred at a lower rate in the semaglutide vs the placebo group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98). Semaglutide did not reduce incident COVID-19; however, among participants who developed COVID-19, fewer participants treated with semaglutide had COVID-19-related serious adverse events (232 vs 277; P = 0.04) or died of COVID-19 (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96). High rates of infectious deaths occurred during the COVID-19 pandemic, with less infectious death in the semaglutide arm, and resulted in fewer participants in the placebo group being at risk for CV death. CONCLUSIONS: Compared to placebo, patients treated with semaglutide 2.4 mg had lower rates of all-cause death, driven similarly by CV and non-CV death. The lower rate of non-CV death with semaglutide was predominantly because of fewer infectious deaths. These findings highlight the effect of semaglutide on mortality across a broad population of patients with CV disease and obesity. (Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity [SELECT]; NCT03574597).

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial.

BACKGROUND: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. METHODS: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. FINDINGS: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. INTERPRETATION: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. FUNDING: Novo Nordisk.

Semaglutide and Cardiovascular Outcomes by Baseline HbA1c and Change in HbA1c in People With Overweight or Obesity but Without Diabetes in SELECT.

OBJECTIVE: To evaluate the cardiovascular effects of semaglutide by baseline glycated hemoglobin (HbA1c) and change in HbA1c in a prespecified analysis of Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT). RESEARCH DESIGN AND METHODS: In SELECT, people with overweight or obesity and atherosclerotic cardiovascular disease without diabetes were randomized to weekly semaglutide 2.4 mg or placebo. The primary end point of first major adverse cardiovascular event (MACE) (cardiovascular mortality, nonfatal myocardial infarction, or stroke) was reduced by 20% with semaglutide versus placebo. Analysis of outcomes included first MACE, its individual components, expanded MACE (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failure composite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality by baseline HbA1c subgroup and categories of HbA1c change (<-0.3, -0.3 to 0.3, and >0.3 percentage points) from baseline to 20 weeks using the intention-to-treat principle with Cox proportional hazards. RESULTS: Among 17,604 participants (mean age 61.6 years, 72.3% male), baseline HbA1c was <5.7% for 33.5%, 5.7% to <6.0% for 34.6%, and 6.0% to <6.5% for 31.9%. Cardiovascular risk reduction with semaglutide versus placebo was not shown to be different across baseline HbA1c groups and was consistent with that of the overall study for all end points, except all-cause mortality. Cardiovascular outcomes were also consistent across subgroups of HbA1c change. CONCLUSIONS: In people with overweight or obesity and established atherosclerotic cardiovascular disease but not diabetes, semaglutide reduced cardiovascular events irrespective of baseline HbA1c or change in HbA1c. Thus, semaglutide is expected to confer cardiovascular benefits in people with established atherosclerotic cardiovascular disease who are normoglycemic at baseline and/or in those without HbA1c improvements.

Correction: Hypertension genetic risk score is associated with burden of coronary heart disease among patients referred for coronary angiography.

[This corrects the article DOI: 10.1371/journal.pone.0208645.].

Long-term cardiovascular outcomes among immigrants and non-immigrants in cardiac resynchronization therapy: a nationwide study.

AIMS: To date, potential differences in outcomes for immigrants and non-immigrants with a cardiac resynchronization therapy (CRT), in a European setting, remain underutilized and unknown. Hence, we examined the efficacy of CRT measured by heart failure (HF)-related hospitalizations and all-cause mortality among immigrants and non-immigrants. METHODS AND RESULTS: All immigrants and non-immigrants who underwent first-time CRT implantation in Denmark (2000-2017) were identified from nationwide registries and followed for up to 5 years. Differences in HF related hospitalizations and all-cause mortality were evaluated by Cox regression analyses. From 2000 to 2017, 369 of 10 741 (3.4%) immigrants compared with 7855 of 223 509 (3.5%) non-immigrants with a HF diagnosis underwent CRT implantation. The origins of the immigrants were Europe (61.2%), Middle East (20.1%), Asia-Pacific (11.9%), Africa (3.5%), and America (3.3%). We found similar high uptake of HF guideline-directed pharmacotherapy before and after CRT and a consistent reduction in HF-related hospitalizations the year before vs. the year after CRT (61% vs. 39% for immigrants and 57% vs. 35% for non-immigrants). No overall difference in 5-year mortality among immigrants and non-immigrants was seen after CRT [24.1% and 25.8%, respectively, P-value = 0.50, hazard ratio (HR) = 1.2, 95% confidence interval (CI): 0.8-1.7]. However, immigrants of Middle Eastern origin had a higher mortality rate (HR = 2.2, 95% CI: 1.2-4.1) compared with non-immigrants. Cardiovascular causes were responsible for the majority of deaths irrespective of immigration status (56.7% and 63.9%, respectively). CONCLUSION: No overall differences in efficacy of CRT in improving outcomes between immigrants and non-immigrants were identified. Although numbers were low, a higher mortality rate among immigrants of Middle Eastern origin was identified compared with non-immigrants.

Hemodialysis and its impact on patient characteristics, microbiology, cardiac surgery, and mortality in infective endocarditis.

BACKGROUND: Patients with chronic renal failure on hemodialysis carry a significant risk of infective endocarditis (IE), but data on whether these patients differ from other patients with IE in terms of comorbidity, microbiology, rates of surgery and mortality are sparse. METHODS: Using Danish nationwide registries, all patients with IE diagnosed between February 1, 2010, and May 14, 2018 were identified and categorized into a "hemodialysis group" and a "non-hemodialysis group." Patient groups were compared by comorbidities, microbiological etiology, cardiac surgery, and mortality. Risk factors associated with mortality were assessed in multivariable Cox regression analysis. RESULTS: In total, 4,366 patients with IE were included with 226 (5.2%) patients in the hemodialysis group. Patients in the hemodialysis group were younger (66.0 years [IQR 53.8-74.9] vs 72.2 years [IQR 62.2-80.0]), had more comorbidities and were surgically treated less often (10.6% vs 20.8%), compared with patients from the nonhemodialysis group. Staphylococcus aureus was more than twice as prevalent (58.0% vs 26.5%). No difference in in-hospital mortality was found between the 2 groups (20.8% vs 18.5%), but 1- and 5-year mortality were significantly higher in the hemodialysis group than in the nonhemodialysis group (37.7% vs 17.7% and 72.1% vs 42.5%, respectively). In adjusted analysis, hemodialysis was associated with higher 1-year (HR = 2.71, 95% CI 2.07-3.55) and 5-year mortality (HR = 2.72, 95% CI 2.22-3.34) CONCLUSIONS: Patients with IE on chronic hemodialysis were younger, had more comorbidity, a higher prevalence of Staphylococcus aureus IE, and a higher mortality than patients without hemodialysis.

Patient characteristics and long-term outcomes in patients undergoing transcatheter aortic valve implantation in a failed surgical prosthesis vs in a native valve: A Danish nationwide study.

BACKGROUND: Valve-in-valve-transcatheter aortic valve implantation (TAVI) is a feasible and increasingly used treatment option for failed surgical aortic prosthesis, but data from clinical practice are limited. We aimed to examine patient characteristics and outcomes of patients undergoing TAVI in a surgival valve (valve-in-valve TAVI) compared with patients undergoing TAVI in a native valve. METHODS: Using nationwide registries, we identified all Danish citizens, who underwent TAVI from January 1, 2008, to December 31, 2020. RESULTS: A total of 6,070 patients undergoing TAVI were identified; 247 (4%) patients had a history of SAVR (The valve-in-valve cohort). The median age of the study population was 81 (25th-75th percentile 77-85) and 55% were men. Patients with valve-in-valve-TAVI were younger but had a greater burden of cardiovascular comorbidities compared with patients with native-valve-TAVI. Within 30 days post procedure, 11 (0.2%) and 748 (13.8%) patients who underwent valve-in-valve-TAVI and native-valve-TAVI, respectively, had a pacemaker implantation. The cumulative 30-day risk of death among patients with valve-in-valve-TAVI was 2.4% (95% CI: 1.0%-5.0%) and 2.7% (95% CI: 2.3%-3.1%) in patients with native-valve-TAVI, respectively. Correspondingly, the cumulative 5-year risk of death was 42.5% (95% CI: 34.2%-50.6%) and 44.8% (95% CI: 43.2%-46.4%), respectively. In multivariable Cox proportional hazard analysis, valve-in-valve-TAVI was not associated with a significantly different risk of death at 30 days (Hazard ratio (HR) = 0.95, 95% CI 0.41-2.19) and 5 years (HR = 0.79, 95% CI 0.62-1.00) post-TAVI compared with native-valve-TAVI. CONCLUSIONS: TAVI in a failed surgical aortic prosthesis as compared to TAVI in a native valve, was not associated with significantly different short- and long-term mortality, suggesting that valve-in-valve-TAVI is a safe procedure.

Severity of Brugada syndrome disease manifestation and risk of new-onset depression or anxiety: a Danish nationwide study.

AIMS: Reduced psychological health is associated with adverse patient outcomes and higher mortality. We aimed to examine if a Brugada syndrome (BrS) diagnosis and symptomatic disease presentation were associated with an increased risk of new-onset depression or anxiety and all-cause mortality. METHODS AND RESULTS: All Danish patients diagnosed with BrS (2006-2018) with no history of psychiatric disease and available for ≥6 months follow-up were identified using nationwide registries and followed for up to 5 years after diagnosis. The development of clinical depression or anxiety was evaluated using the prescription of medication and diagnosis codes. Factors associated with developing new-onset depression or anxiety were determined using a multivariate Cox proportional hazards regression model. Disease manifestation was categorized as symptomatic (aborted cardiac arrest, ventricular tachycardia, or syncope) or asymptomatic/unspecified at diagnosis. A total of 223 patients with BrS and no history of psychiatric disease were identified (72.6% male, median age at diagnosis 46 years, 45.3% symptomatic). Of these, 15.7% (35/223) developed new-onset depression or anxiety after BrS diagnosis (median follow-up 5.0 years). A greater proportion of symptomatic patients developed new-onset depression or anxiety compared with asymptomatic patients [21/101 (20.8%) and 14/122 (11.5%), respectively, P = 0.08]. Symptomatic disease presentation (HR 3.43, 1.46-8.05) and older age (lower vs. upper tertile: HR 4.41, 1.42-13.63) were significantly associated with new-onset depression or anxiety. All-cause mortality in this group of patients treated according to guidelines was low (n = 4, 1.8%); however, 3/4 developed depression or anxiety before death. CONCLUSION: Approximately, one-sixth of patients with BrS developed new-onset depression or anxiety following a diagnosis of BrS. Symptomatic BrS disease manifestation was significantly associated with new-onset depression or anxiety.

Ventricular rate in atrial fibrillation and the risk of heart failure and death.

AIMS: While clinical trials have suggested that a high ventricular rate is associated with increased risk of heart failure (HF) and mortality, all-comers studies are warranted. OBJECTIVE: To assess 1-year risk of new-onset diagnosed HF and all-cause mortality among rate-control treated patients presenting with atrial fibrillation (AF) on an electrocardiogram (ECG) according to ventricular rate. METHODS AND RESULTS: ECGs recorded at the Copenhagen General Practitioners Laboratory (2001-15) were used to identify patients with AF. Multivariate Cox proportional hazard regression models were used to compare risk of new-onset HF and all-cause mortality after first ECG presenting with AF according to ventricular rate on ECG [<60, 60-79, 80-99, and 100-110, > 110 beats per minute (bpm)]. We identified 7408 patients in treatment with rate control drugs at time of first ECG presenting with AF [median age 78 years (Q1,Q3 = 70-85 years)], 45.8% male, median ventricular rate 83 bpm, (Q1,Q3 = 71-101 bpm)]. During 1-year follow-up, 666 (9.0%) of all patients with AF developed HF and 858 (11.6%) died. Patients with AF ventricular rates 100-110 bpm and >110 bpm had a hazard ratio (HR) of 1.46 (CI: 1.10-1.95) and 2.41 (CI: 1.94-3.00) respectively for new-onset HF, compared with 60-79 bpm. Similarly, patients with AF ventricular rates 100-110 bpm and >110 bpm had a HR of 1.44 (CI: 1.13-1.82) and 1.34 (CI: 1.08-1.65) respectively for all-cause mortality, compared with 60-79 bpm. CONCLUSIONS: Ventricular rates ≥100 bpm among patients presenting with AF on ECG in treatment with rate control drugs were associated with greater risk of both new-onset HF and all-cause mortality.

Temporal changes in incidence, treatment strategies and 1-year re-admission rates in patients with atrial fibrillation/flutter under 65 years of age: A Danish nationwide study.

AIM: To examine temporal changes in incidence rates of atrial fibrillation/flutter (AF), treatment strategies, and AF readmission rates in patients <65 years. METHODS: Using Danish nationwide registries, we identified patients <65 years with a first-time AF diagnosis from 2000 to 2018. The cohort was categorized according to calendar periods; 2000-2002, 2003-2006, 2007-2010, 2011-2014, and 2015-2018. In this retrospective cohort study the incidence rate (IR) of AF per 100,000 person years (PY), catheter ablation, electrical cardioversion, use of pharmacotherapy, and AF readmission, were investigated in the first year following AF diagnosis. RESULTS: We identified 60,917 patients; 8150 (13.4%) in 2000-2002, 11,898 (19.5%) in 2003-2006, 13,560 (22.3%) in 2007-2010, 14,167 (23.3%) in 2011-2014, and 13,142 (21.6%) in 2015-2018. Apart from 2015 to 2018, a stepwise increase in the crude IR of AF was observed across calendar periods; 2000-2002: 78.7 (95% CI 77.0;80.4), 2003-2006: 86.3 (84.7;87.8), 2007-2010: 97.9 (96.3;99.6), 2011-2014: 102.3 (100.7;104.0), 2015-2018: 93.6 (92.0;95.2). Over the studied time-periods, we found a stepwise increase in the cumulative incidence of catheter ablation (1.2% to 7.6%) electrical cardioversion (2.0% to 8.7%) and treatment with oral anticoagulant therapy (OAC) (28.5% to 47.8%) within the first year of diagnosis. No temporal differences in incidence of 1-year AF readmission were identified (AF-readmissions: 2000-2002: 32.7%, 2003-2006: 31.1%, 2007-2010: 32.2%, 2011-2014: 32.1% and 2015-2018: 31.7%). CONCLUSION: The incidence rate of AF in patients <65 years increased from 2000 to 2018, as did the use of catheter ablation, electrical cardioversion and OAC in the first year following AF diagnosis. 1-year AF readmission incidence remained stable around 32% over the study period.

Use of Nonrecommended Drugs in Patients With Brugada Syndrome: A Danish Nationwide Cohort Study.

Background Patients with Brugada syndrome (BrS) are recommended to avoid drugs that may increase their risk of arrhythmic events. We examined treatment with such drugs in patients with BrS after their diagnosis. Methods and Results All Danish patients diagnosed with BrS (2006-2018) with >12 months of follow-up were identified from nationwide registries. Nonrecommended BrS drugs were grouped into drugs to "avoid" or "preferably avoid" according to http://www.brugadadrugs.org. Cox proportional hazards analyses were performed to identify factors associated with any nonrecommended BrS drug use, and logistic regression analyses were performed to examine associated risk of appropriate implantable cardioverter defibrillator therapy, mortality, and a combined end point indicating an arrhythmic event of delayed implantable cardioverter defibrillator implantation, appropriate implantable cardioverter defibrillator therapy, and mortality. During a median follow-up of 6.8 years, 93/270 (34.4%) patients with BrS (70.4% male, median age at diagnosis 46.1 years [interquartile range, 32.6-57.4]) were treated with ≥1 nonrecommended BrS drugs. No difference in any nonrecommended BrS drug use was identified comparing time before BrS diagnosis (12.6%) with each of the 5 years following BrS diagnosis (P>0.05). Factors associated with any nonrecommended BrS drug use after diagnosis were female sex (hazard ratio [HR]) 1.83 [95% CI, 1.15-2.90]), psychiatric disease (HR, 3.63 [1.89-6.99]), and prior use of any nonrecommended BrS drug (HR, 4.76 [2.45-9.25]). No significant association between any nonrecommended BrS drug use and implantable cardioverter defibrillator therapy (n=20/97, odds ratio [OR], 0.7 [0.2-2.4]), mortality (n=10/270, OR, 3.4 [0.7-19.6]), or the combined end point (n=38/270, OR, 1.7 [0.8-3.7]) was identified. Conclusions One in 3 patients with BrS were treated with a nonrecommended BrS drug after BrS diagnosis, and a BrS diagnosis did not change prescription patterns. More awareness of nonrecommended drug use among patients with BrS is needed.

Incidence of thyroid dysfunction following initiation of amiodarone treatment in patients with and without heart failure: a nationwide cohort study.

AIMS: Thyroid dysfunction is considered the most frequent complication to amiodarone treatment, but data on its occurrence outside clinical trials are sparse. The present study aimed to examine the incidence of thyroid dysfunction following initiation of amiodarone treatment in a nationwide cohort of patients with and without heart failure (HF). METHODS AND RESULTS: In Danish registries, we identified all patients with first-time amiodarone treatment during the period 2000-18, without prior thyroid disease or medication. The primary outcome was a composite of thyroid diagnoses and initiation of thyroid drugs. Outcomes were assessed at 1-year follow-up, and for patients free of events in the first year, in a landmark analysis for the subsequent 5 years. We included 43 724 patients with first-time amiodarone treatment, of whom 16 939 (38%) had HF. At 1-year follow-up, the cumulative incidence and adjusted hazard ratio (HR) of the primary outcome were 5.3% and 1.37 (95% confidence interval 1.25-1.50) in patients with a history of HF and 4.2% in those without HF (reference). In the 1-year landmark analysis, the subsequent 5-year cumulative incidences and adjusted HRs of the primary outcome were 5.3% (reference) in patients with 1-year accumulated dose <27.38 g [corresponding to average daily dose (ADD <75 mg)], 14.0% and HR 2.74 (2.46-3.05) for 27.38-45.63 g (ADD 75-125 mg), 20.0% and HR 4.16 (3.77-4.59) for 45.64-63.88 g (ADD 126-175 mg), and 24.5% and HR 5.30 (4.82-5.90) for >63.88 g (ADD >175 mg). CONCLUSION: Among patients who initiated amiodarone treatment, around 5% had thyroid dysfunction at 1-year follow-up, with a slightly higher incidence in those with HF. A dose-response relationship was observed between the 1-year accumulated amiodarone dose and the subsequent 5-year cumulative incidence of thyroid dysfunction.

Use of torsades de pointes risk drugs among patients with out-of-hospital cardiac arrest and likelihood of shockable rhythm and return of spontaneous circulation: A nationwide study.

AIM: Treatment with certain drugs can augment the risk of developing malignant arrhythmias (e.g. torsades de pointes [TdP]). Hence, we examined the overall TdP risk drug use before out-of-hospital cardiac arrest (OHCA) and possible association with shockable rhythm and return of spontaneous circulation (ROSC). METHODS: Patients ≥18 years with an OHCA of cardiac origin from the Danish Cardiac Arrest Registry (2001-2014) and TdP risk drug use according to www.CredibleMeds.org were identified. Factors associated with TdP risk drug use and secondly how use may affect shockable rhythm and ROSC were determined by multivariable logistic regression. RESULTS: We identified 27,481 patients with an OHCA of cardiac origin (median age: 72 years [interquartile range 62.0, 80.0 years]). A total of 37% were in treatment with TdP risk drugs 0-30 days before OHCA compared with 33% 61-90 days before OHCA (p < 0.001). Most commonly used TdP risk drugs were citalopram (36.1%) and roxithromycin (10.7%). Patients in TdP risk drug treatment were older (75 vs 70 years) and more comorbid compared with those not in treatment. Subsequently, TdP risk drug use was associated with less likelihood of the presenting rhythm being shockable (odds ratio [OR] = 0.63, 95% confidence interval [CI]:0.58-0.69) and ROSC (OR = 0.73, 95% CI:0.66-0.80). CONCLUSION: TdP risk drug use increased in the time leading up to OHCA and was associated with reduced likelihood of presenting with a shockable rhythm and ROSC in an all-comer OHCA setting. However, patients in TdP risk drug treatment were older and more comorbid than patients not in treatment.

Workforce attachment after a congenital long QT syndrome diagnosis: a Danish nationwide study.

OBJECTIVE: To examine workforce attachment among patients with congenital long QT syndrome (cLQTS) following diagnosis and identify factors associated with workforce attachment. METHODS AND RESULTS: In this nationwide cohort study, all patients diagnosed with cLQTS in Denmark between 1996 and 2016 aged 18-60 years at diagnosis were identified using nationwide registries. Patients attached to the workforce at diagnosis were included. Attachment to the workforce 1 year after cLQTS diagnosis was examined and compared with a background population matched 1:4 on age, sex and employment status. Multiple logistic regression was performed to identify factors associated with 1-year workforce detachment among patients with cLQTS. 298 patients fulfilled the inclusion criteria. Six months after cLQTS diagnosis, 90.9% of patients with cLQTS were attached to the workforce compared with 95.0% in the background population (p=0.006 for difference). One year after diagnosis, 93.3% of patients with cLQTS were attached to the workforce compared with 93.8% in the background population (p=0.26). Among patients with cLQTS, a severe cLQTS disease manifestation was associated with workforce detachment 1 year after diagnosis (compared with asymptomatic patients; aborted cardiac arrest OR 20.4 (95% CI, 1.7 to 249.9); ventricular tachycardia/syncope OR 10.9 (95% CI, 1.1 to 110.5)). No other associated factors were identified. CONCLUSIONS: More than 90% of patients with cLQTS remained attached to the workforce 1 year after diagnosis, which was similar to a matched background population. Patients with a severe cLQTS disease manifestation were less likely to be attached to the workforce 1 year after diagnosis.

Return to work after acute myocardial infarction with cardiogenic shock: a Danish nationwide cohort study.

BACKGROUND: Physical and mental well-being after critical illness may be objectified by the ability to work. We examined return to work among patients with myocardial infarction (MI) by cardiogenic shock (CS) status. METHODS: Danish nationwide registries were used to identify patients with first-time MI by CS status between 2005 and 2015, aged 18-63 years, working before hospitalization and discharged alive. Multiple logistic regression models were used to compare groups. RESULTS: We identified 19 799 patients with MI of whom 653 had CS (3%). The median age was similar for patients with and without CS (53 years, interquartile range 47-58). One-year outcomes in patients with and without CS were as follows: 52% vs. 83% returned to work, 41% vs. 16% did not and 6% vs. 1% died. The adjusted odds ratio (OR) of returning to work was 0.53 [95% confidence limit (CI): 0.42-0.66]. In patients with CS, males and patients surviving OHCA were more likely to return to work (OR: 1.83, 95% CI: 1.15-2.92 and 1.55, 95% CI: 1.00-2.40, respectively), whereas prolonged hospitalization (OR: 0.38, 95% CI: 0.22-0.65) and anoxic brain damage (OR: 0.36, 95% CI: 0.18-0.72) were associated with lower likelihood of returning to work. CONCLUSION: In patients with MI discharged alive, approximately 80% of those without CS returned to work at 1-year follow-up in contrast to 50% of those with CS. Among patients with CS, male sex and OHCA survivors were markers positively related to return to work, whereas prolonged hospitalization and anoxic brain damage were negatively related markers.

ß-blocker adherence among patients with congenital long QT syndrome: a nationwide study.

AIM: ß-blockers are the first line of treatment in patients with congenital long QT syndrome (cLQTS) (class I or II recommendation) in order to prevent malignant arrhythmias. Hence, we examined long-term ß-blocker adherence and associated risk factors among patients with cLQTS. METHODS AND RESULTS: Danish patients with cLQTS claiming a prescription for any ß-blocker after their cLQTS diagnosis were identified using data from nationwide registries and specialized inherited cardiac disease clinics (1995-2017). Patients were followed for up to 5 years. Treatment breaks >60 days were assessed (i.e. proxy for reduced adherence). Multivariable Cox regression was used to identify risk factors associated with breaks of >60 days in ß-blocker treatment. Overall, 500 out of 633 (79%) patients with cLQTS claimed at least one prescription for any ß-blocker after cLQTS diagnosis. During follow-up, 38.4% had a treatment break. Risk factors significantly associated with treatment breaks were implantable cardioverter defibrillator (ICD) [hazard ratio (HR) = 1.65, 95% confidence interval (CI): 1.08-2.53], ß-blocker side effects (HR = 2.69, 95% CI: 1.75-4.13), and psychiatric disease (HR = 1.63, 95% CI: 1.04-2.57). In contrast, patients presenting with ventricular tachycardia/syncope as cLQTS disease manifestation were less likely to have a treatment break compared with asymptomatic patients (HR = 0.55, 95% CI: 0.33-0.92). CONCLUSION: Reduced ß-blocker adherence was common with more than a third of patients having a treatment break >60 days after cLQTS diagnosis. Patients with psychiatric disease, self-reported ß-blocker side effects, and an ICD were more likely to display reduced adherence, whereas a severe cLQTS disease manifestation was associated with optimal ß-blocker adherence.

Association Between Inappropriately Dosed Anticoagulation Therapy With Stroke Severity and Outcomes in Patients With Atrial Fibrillation.

Background Oral anticoagulation (OAC) is effective for stroke prevention in patients with atrial fibrillation. However, some patients experience stroke despite OAC therapy, and knowledge about the impact of prior treatment quality is lacking. Methods and Results Patients with atrial fibrillation on OAC therapy who had a first-time ischemic stroke were identified in the Danish Stroke Registry (2005-2018). Patients treated with vitamin K antagonist (VKA) therapy were compared according to the international normalized ratio just before stroke (international normalized ratio <2 [subtherapeutic], international normalized ratio 2-3 [therapeutic], international normalized ratio >3 [supratherapeutic]), and patients on underdosed, appropriately dosed, and overdosed direct OAC (DOAC) therapy were compared. Stroke severity was determined using the Scandinavia Stroke Scale (0-58 points), and the risk of very severe stroke (0-14 points) was analyzed by multivariable logistic regression. One-year mortality was determined using multivariable Cox regression. A total of 2319 patients with atrial fibrillation and stroke were included; 1196 were taking a VKA (subtherapeutic [46%], therapeutic [43%], supratherapeutic [11%]), and 1123 were taking DOAC (underdosed [23%], appropriately dosed [60%], and overdosed [17%]). Subtherapeutic and supratherapeutic VKA therapy (compared with therapeutic) and underdosed DOAC therapy (compared with appropriate and underdosed DOAC) patients were older, more often women, and more comorbid. Subtherapeutic VKA therapy was associated with very severe stroke (odds ratio [OR], 2.06 [95% CI, 1.28-3.31]), whereas supratherapeutic VKA therapy was not (OR, 1.24 [95% CI, 0.60-2.57]) compared with therapeutic VKA therapy. Patients on subtherapeutic and supratherapeutic VKA therapy had a higher 1-year mortality (hazard ratio [HR], 1.66 [95% CI, 1.29-2.13]); HR, 1.55 [95% CI, 1.08-2.22], respectively) than those on therapeutic VKA therapy. Treatment with underdosed or overdosed DOAC therapy was not associated with very severe stroke (OR, 1.27 [95% CI, 0.76-2.15]; OR, 0.73 [95% CI, 0.37-1.43], respectively) and was not associated with 1-year mortality (HR, 1.09 [95% CI, 0.83-1.44]; HR, 0.82 [95% CI, 0.57-1.18], respectively) than appropriate DOAC. Conclusions Half of the patients with atrial fibrillation with stroke were on inappropriate OAC therapy. Subtherapeutic VKA was associated with worse stroke severity and higher mortality rate than therapeutic VKA therapy. Neither underdosed nor overdosed DOAC was associated with worse outcomes in adjusted models compared with appropriately dosed DOAC. This study supports DOAC as a first-line therapy over VKA.

Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

Cause-specific death and risk factors of 1-year mortality after implantable cardioverter-defibrillator implantation: a nationwide study.

AIMS: Current treatment guidelines recommend implantable cardioverter-defibrillators (ICDs) in eligible patients with an estimated survival beyond 1 year. There is still an unmet need to identify patients who are unlikely to benefit from an ICD. We determined cause-specific 1-year mortality after ICD implantation and identified associated risk factors. METHODS AND RESULTS: Using Danish nationwide registries (2000-2017), we identified 14 516 patients undergoing first-time ICD implantation for primary or secondary prevention. Risk factors associated with 1-year mortality were evaluated using multivariable logistic regression. The median age was 66 years, 81.3% were male, and 50.3% received an ICD for secondary prevention. The 1-year mortality rate was 4.8% (694/14 516). ICD recipients who died within 1 year were older and more comorbid compared to those who survived (72 vs. 66 years, P < 0.001). Risk factors associated with increased 1-year mortality included dialysis [odds ratio (OR): 3.26, confidence interval (CI): 2.37-4.49], chronic renal disease (OR: 2.14, CI: 1.66-2.76), cancer (OR: 1.51, CI: 1.15-1.99), age 70-79 years (OR: 1.65, CI: 1.36-2.01), and age ≥80 years (OR: 2.84, CI: 2.15-3.77). The 1-year mortality rates for the specific risk factors were: dialysis (13.8%), chronic renal disease (13.1%), cancer (8.5%), age 70-79 years (6.9%), and age ≥80 years (11.0%). Overall, the most common causes of mortality were related to cardiovascular diseases (62.5%), cancer (10.1%), and endocrine disorders (5.0%). However, the most common cause of death among patients with cancer was cancer-related (45.7%). CONCLUSION: Among ICD recipients, mortality rates were low and could be indicative of relevant patient selection. Important risk factors of increased 1-year mortality included dialysis, chronic renal disease, cancer, and advanced age.