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BACKGROUND: Data concerning the long-term risk of heart failure (HF) in patients with takotsubo syndrome (TTS) are sparse. We compared the rates of death and hospitalization due to HF with matched individuals from the background population and patients with ST-segment elevation myocardial infarction (STEMI).METHODS: In this nationwide observational cohort study, all patients with first-time TTS (2011-2018) who were alive at discharge were identified by using data from Danish nationwide registries. These were matched for age and sex with individuals from the background population (1:4 matching) and with patients with STEMI who were alive at discharge (1:3 matching).RESULTS: A total of 881 patients with TTS who were alive at discharge were identified (median age 70 years; 89.4% men). During a mean follow-up of 2.9 years, the incidence rates of death, HF hospitalization, and TTS recurrence in survivors of TTS were 6.9, 0.9 and 1.1 events per 100 person-years. The corresponding absolute 3-year risks were 9.3%, 1.8% and 2.5%, respectively. Survivors of TTS had higher associated rates of death compared with the background population (hazard ratio [HR] 2.05 [95% CI, 1.62-2.60]) and survivors of STEMI (HR 1.69 [1.34-2.13]). Similarly, survivors of TTS had higher associated rates of hospitalization due to HF compared with the background population (HR 4.24 [1.88-9.53]), but lower rates compared with survivors of STEMI (HR 0.34 [0.20-0.56]). Propensity-score matched analyses yielded similar results.CONCLUSIONS: Survivors of TTS had significantly higher associated mortality rates than the background population and survivors of STEMI. Survivors of TTS had lower HF hospitalization rates than survivors of STEMI, but the rates were higher than those of the background population.

Updated guidelines on diabetes recommend targeting sodium-glucose cotransporter-2 inhibitors (SGLT2i) at patients at risk of heart failure (HF) and glucagon-like peptide-1 receptor agonists (GLP1-RA) at those at greater risk of atherothrombotic events.We estimated the risk of different cardiovascular events in patients with type 2 diabetes (T2D) and newly established cardiovascular disease.Patients with T2D and newly established cardiovascular disease from 1998 to 2016 were identified using Danish healthcare registers and divided into one of four phenotype groups: (1) HF, (2) ischemic heart disease (IHD), (3) transient ischemic stroke (TIA)/ischemic stroke, and (4) peripheral artery disease (PAD). The absolute 5-year risk of the first HF- or atherothrombotic event occurring after inclusion was calculated, along with the risk of death.The main outcome was the first event of either HF or an atherothrombotic event (IHD, TIA/ischemic stroke or PAD) in patients with T2D and new-onset cardiovascular disease.Of the 37,850 patients included, 40% were female and the median age was 70 years. Patients with HF were at higher 5-year risk of a subsequent HF event (17.9%; 95% confidence interval (CI) 17.1-18.8%) than an atherothrombotic event (15.8%; 15.0-16.6%). Patients with IHD were at higher risk of a subsequent atherothrombotic event (24.6%; 23.9-25.3%) than developing HF, although the risk of HF was still substantial (10.6%; 10.2-11.1%). Conversely, patients with PAD were at low risk of developing HF (4.4%; 3.8-5.1%) but at high risk of developing an atherothrombotic event (15.9%; 14.9-17.1%). Patients with TIA/ischemic stroke had the lowest risk of HF (3.2%; 2.9-3.6%) and the highest risk of an atherothrombotic event (20.6%; 19.8-21.4).In T2D, a patient's cardiovascular phenotype can help predict the pattern of future cardiovascular events.

The prognostic importance of new-onset type 2 diabetes (T2D) in heart failure (HF) remains unknown. We aimed to describe the cardiovascular outcome profile in HF patients with new-onset, no and prevalent T2D.We constructed a cohort of patients with first HF admission between 1998 and 2016 from nationwide Danish registers. Outcomes were ischemic event, HF event, and death from other causes. The landmarking approach and the Aalen Johansen estimator were used together to estimate 5-year absolute and 5-year relative risk of the outcomes in HF patients with new-onset, no and prevalent T2D. Risk among subgroups were investigated by stratification.A total of 139 264 HF patients were included between 1998 and 2016, of which 29 078 patients had prevalent T2D. A total of 11 819 developed new-onset T2D. The 5-year risks of ischemic event in new-onset, no, and prevalent T2D were: 17.9% [17.2; 18.6], 18.8% [18.6; 19.0], and 26.1% [25.6; 26.7]. The 5-year risks of HF event were: 31.5% [30.6; 32.3], 30.7% [30.5; 31.0], and 33.6% [33.0; 34.2]. For other causes of death, the 5-year risks were: 20.9% [20.2; 21.7], 18.6% [18.4; 18.8], and 18.9% [18.4; 19.3]. The 5-year risk ratios of HF event or death from other causes versus ischemic event were: 2.9 [2.8; 3.1], 2.6 [2.6; 2.7], and 2.0 [2.0; 2.1] in patients with new-onset, no, and prevalent T2D.In patients with new-onset T2D, death from other causes were more likely to occur than an ischemic event, whereas in patients with prevalent T2D and no T2D, ischemic events were more common.

Aim: There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre-diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre-diabetes in PARAGON-HF.Methods and results: Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, Conclusion: Pre-diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711.

AimsThyroid 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 resultsIn 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 63.88 g (ADD >175 mg).ConclusionAmong 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.

Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( 3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

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.

Background Data on long-term cardiovascular outcomes in systemic lupus erythematosus (SLE) are sparse. Objectives This study sought to examine the long-term risk and prognosis associated with cardiovascular outcomes, including heart failure (HF), in patients with SLE. Methods Using Danish administrative registries, risks of outcomes were compared between SLE patients (diagnosed 1996 to 2018, no history of cardiovascular disease) and age-, sex-, and comorbidity-matched control subjects from the background population (matched 1:4). Furthermore, mortality following HF diagnosis was compared between SLE patients developing HF and age- and sex-matched non-SLE control subjects with HF (matched 1:4). Results A total of 3,411 SLE patients (median age: 44.6 years [25th to 75th percentile: 31.9 to 57.0 years]; 14.1% men) were matched with 13,644 control subjects. The median follow-up was 8.5 years (25th to 75th percentile: 4.0 to 14.4 years). Absolute 10-year risks of outcomes were: HF, 3.71% (95% confidence interval [CI]: 3.02% to 4.51%) for SLE patients, 1.94% (95% CI: 1.68% to 2.24%) for control subjects; atrial fibrillation, 4.35% (95% CI: 3.61% to 5.18%) for SLE patients, 2.82% (95% CI: 2.50% to 3.16%) for control subjects; ischemic stroke, 3.75% (95% CI: 3.06% to 4.54%) for SLE patients, 1.92% (95% CI: 1.66% to 2.20%) for control subjects; myocardial infarction, 2.17% (95% CI: 1.66% to 2.80%) for SLE patients, 1.49% (95% CI: 1.26% to 1.75%) for control subjects; venous thromboembolism, 6.03% (95% CI: 5.17% to 6.98%) for SLE patients, 1.68% (95% CI: 1.44% to 1.95%) for control subjects; and the composite of implantable cardioverter-defibrillator implantation/ventricular arrhythmias/cardiac arrest, 0.89% (95% CI: 0.58% to 1.31%) for SLE patients, 0.30% (95% CI: 0.20% to 0.43%) for control subjects. SLE with subsequent HF was associated with higher mortality compared with HF without SLE (adjusted hazard ratio: 1.50; 95% CI: 1.08 to 2.08). Conclusions SLE patients had a higher associated risk of HF and other cardiovascular outcomes compared with matched control subjects. Among patients developing HF, a history of SLE was associated with higher mortality.

Objectives The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. Background MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination. Methods A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. Results A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m2), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction = 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. Conclusions Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124 )

Objectives We examined loop diuretic treatment before and 1-year after transcatheter aortic valve implantation (TAVI), as a proxy for changes in symptom severity and secondly assessed how changes in loop diuretics related to mortality risk. Background Randomized clinical trials suggest that approximately one third of patients undergoing TAVI do not achieve symptom relief, but “all-comer” data are lacking. Methods Using Danish nationwide registries, we identified all citizens, who underwent TAVI from 2008 to 2019 and were alive at 1-year post-discharge. Loop diuretic treatment pre-TAVI and at 1-year post-TAVI were assessed and grouped as receiving 1) no-loop diuretics; 2) low: 1–40 mg of furosemide (or equivalent bumetanide) daily; 3) intermediate: 41–120 mg of furosemide daily; or 4) high: >120 mg furosemide daily. Results Among the 4431 patients undergoing TAVI, 2173 (49%) patients were not treated with loop diuretics at the time of TAVI, 918 (21%) had low-loop diuretics, 881 (20%) had intermediate-loop diuretics, and 459 (10%) had high-loop diuretics. At 1-year post-TAVI, 893 (20%) patients had increased, 1010 (23%) had reduced, and 2528 (57%) had unchanged loop diuretic treatment. The cumulative 5-year risk of death in patients surviving one year, was 61% (95% CI: 56.4% to 65.3%) in patients with increased and 47% (95% CI: 44.9% to 49.9%) in patients with reduced/unchanged loop diuretic treatment, respectively. In multivariable Cox proportional hazard analysis, increased loop diuretic treatment was associated with a higher risk of death compared with reduced/unchanged loop diuretic treatment (Hazard ratio: 1.4; 95% CI: 1.22 to 1.52). Conclusions Among patients undergoing TAVI, surviving one year, one fifth of patients had increased loop diuretic treatment, and a little over one fifth had reduced loop diuretic treatment 1-year post-procedure. In patients with increased diuretic treatment, the risk of death was higher compared to those with reduced/unchanged loop diuretic treatment.

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 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.

Background In Danish administrative registers, ejection fraction (EF) is not recorded, which is a considerable limitation for correct subclassification of patients with heart failure (HF). We hypothesized that a diagnosis of HF combined with the recorded prescription of both renin-angiotensin system (RAS) inhibitors and beta- blockers (RASi+BB) within 120 days could identify patients with HF and reduced ejection fraction (EF ≤40%) (HFrEF). Methods On two sites, we identified all patients with a first-time registration of HF as primary hospital discharge diagnosis (ICD-10: I50) between June 1, 2016, and May 31, 2018 in inpatient or outpatient settings. Patients were included if they survived the initial 120 days after discharge. Reviewing patient records, we identified patients with HFrEF, based on EF ≤ 40% and reported HF symptoms. We registered the use of RASi+BB at 120 days and calculated sensitivity, specificity and predictive values. Results A total of 704 consecutive patients with a primary diagnosis of HF were included, of whom 541 (77%) fulfilled the HFrEF criteria. Patients with HFrEF confirmed from patient records were younger (median age 73 compared to 79 years) and less frequently women (31% compared to 56%) compared to non-HFrEF patients. At baseline, 24 (4%) of HFrEF patients were treated with RASi+BB compared to 22 (14%) of non-HFrEF patients. At 120 days, 460 (85%) of HFrEF patients received RASi+BB as compared to 25 (15%) of non-HFrEF patients. This resulted in a positive predictive value of 95%, sensitivity of 85% and specificity of 85%. Conclusion In Denmark, the ICD-10 HF diagnosis combined with recorded RASi+BB treatment by 120 days after discharge has high positive predictive value and can accurately be used to identify patients with HFrEF.

ObjectiveTo examine the long-term rates of heart failure (HF) and other adverse cardiovascular (CV) outcomes in a nationwide cohort of patients diagnosed with granulomatosis with polyangiitis (GPA) compared with the general population.MethodsUsing Danish nationwide registries, patients with newly diagnosed GPA were identified and matched 1:4 by age, sex, and comorbidities with subjects from the general population. Outcomes were compared using Cox regression. Due to violation of the proportional hazard assumption, landmark analyses for the first year and from 1 year were performed.ResultsOf the 1923 patients with GPA, 1781 patients (median age 59 yrs, 47.9% men) were matched with 7124 subjects from the general population. The median follow-up was 6.4 years. The absolute 10-year risk of HF was 6.8% (95% CI 5.5–8.2%) for patients with GPA and 5.9% (5.3–6.6%) for the general population. During the first year after diagnosis, GPA was associated with a significantly higher rate of HF (hazard ratio [HR] 3.60, 95% CI, 2.28–5.67) and other adverse outcomes, including atrial fibrillation/flutter (HR 6.50, 95% CI 4.43–9.55) and ischemic stroke (HR 3.24, 95% CI 1.92–5.48), compared with the general population. After the first year, GPA was not associated with higher rates of HF or other CV outcomes compared with the general population, except atrial fibrillation/flutter (HR 1.38, 95% CI 1.12-1.70).ConclusionDuring the first year after diagnosis, the rates of HF and other CV outcomes were higher in patients with GPA compared with the general population. However, after the first year, the rates of HF and other CV outcomes, except atrial fibrillation/flutter, were similar to those in the general population.

Background It is poorly understood why some patients with atrial fibrillation develop heart failure (HF) and others do not. We examined the rate of developing HF in patients with atrial fibrillation with and without first‐degree family members with HF or dilated cardiomyopathy (DCM). Methods and Results Using Danish nationwide registries, patients born after 1942 diagnosed with atrial fibrillation in the period 2005 to 2015 were identified and followed for up to 5 years. Patients with pre‐existing HF, DCM, and/or ischemic heart disease diagnoses were excluded. Exposure was defined as a first‐degree relative with HF or DCM. The rate of developing the composite end point of HF or death, and the components, was estimated with multivariable Cox proportional hazard regression models. We included 10 605 patients. A total of 17% had a family member with DCM/HF. Having a family member with HF/DCM was associated with an increased 5‐year risk of the composite of HF/death (cumulative incidence, 9.2% [95% CI, 7.8–10.7] versus 5.6% [95% CI, 5.0–6.1]; adjusted hazard ratio [HR] 1.36 [95% CI, 1.13–1.64]). (HF 8.4% [95% CI, 7.0–9.8] versus 4.5% [95% CI, 4.1–5.0]); (adjusted HR, 1.49 [95% CI, 1.22–1.82]). However, familial HF/DCM was not significantly associated with an increased 5‐year risk and rate of death (0.8% [95% CI, 0.4–1.2] versus 1.1% [95% CI, 0.8–1.3]); (adjusted HR, 0.80 [95% CI, 0.46–1.39]). Conclusions In patients with incident atrial fibrillation without prior ischemic heart disease or HF diagnoses, 1 of 6 had a first‐degree relative with HF, and having such a family history of HF/DCM was associated with an 87% increase in 5‐year incidence of HF compared with those without.

Background: Factors determining referral for advanced heart failure (HF) evaluation are poorly studied. We studied the influence of socioeconomic aspects on the referral process in Denmark, which has a taxpayer-funded national health care system. Methods: We identified all patients aged 18 to 75 years with a first diagnosis of HF during 2010 to 2018. Hospitalized patients had to be discharged alive and were then followed for the outcome of undergoing a right heart catheterization (RHC) used as a surrogate marker of advanced HF work-up. Results: Of 36 637 newly diagnosed patients with HF, 680 (1.9%) underwent RHC during the follow-up period (median time to RHC of 280 days [interquartile range, 73–914]). Factors associated with a higher likelihood of RHC included the highest versus lowest household income quartile (HR, 1.56 [95% CI, 1.19–2.06]; P =0.001), being diagnosed with HF at a tertiary versus nontertiary hospital (HR, 1.68 [95% CI, 1.37–2.05]; P P Conclusions: Higher household income, HF diagnosis during hospitalization, and first admission at a tertiary hospital were associated with increased likelihood of subsequent referral for RHC independent of other demographic and clinical variables. Greater attention may be required to ensure timely referral for advanced HF therapies in lower income groups.

Background Carvedilol may have favorable glycemic properties compared with metoprolol, but it is unknown if carvedilol has mortality benefit over metoprolol in patients with type 2 diabetes (T2D) and heart failure with reduced ejection fraction (HFrEF). Methods and Results Using Danish nationwide databases between 2010 and 2018, we followed patients with new‐onset HFrEF treated with either carvedilol or metoprolol for all‐cause mortality until the end of 2018. Follow‐up started 120 days after initial HFrEF diagnosis to allow initiation of guideline‐directed medical therapy. There were 39 260 patients on carvedilol or metoprolol at baseline (mean age 70.8 years, 35% women), of which 9355 (24%) had T2D. Carvedilol was used in 2989 (32%) patients with T2D and 10 411 (35%) of patients without T2D. Users of carvedilol had a lower prevalence of atrial fibrillation (20% versus 35%), but other characteristics appeared well‐balanced between the groups. Totally 11 306 (29%) were deceased by the end of follow‐up. We observed no mortality differences between carvedilol and metoprolol, multivariable‐adjusted hazard ratio (HR) 0.97 (0.90–1.05) in patients with T2D versus 1.00 (0.95–1.05) for those without T2D, P for difference =0.99. Rates of new‐onset T2D were lower in users of carvedilol versus metoprolol; age, sex, and calendar year adjusted HR 0.83 (0.75–0.91), P Conclusions In a contemporary clinical cohort of HFrEF patients with and without T2D, carvedilol was not associated with a reduction in long‐term mortality compared with metoprolol. However, carvedilol was associated with lowered risk of new‐onset T2D supporting the assertion that carvedilol has a more favorable metabolic profile than metoprolol.

Background Patients with chronic diseases are at higher risk of requiring domiciliary and nursing home care, but how different chronic diseases compare in terms of risk is not known. We examined initiation of domiciliary care and nursing home admission among patients with heart failure (HF), stroke, COPD and cancer. Methods Patients with a first-time hospitalization for HF, stroke, COPD or cancer from 2008–2016 were identified. Patients were matched on age and sex and followed for five years. Results 111,144 patients, 27,786 with each disease, were identified. The median age was 69 years and two thirds of the patients were men. The 5-year risk of receiving domiciliary care was; HF 20.9%, stroke 25.2%, COPD 24.6% and cancer 19.3%. The corresponding adjusted hazard ratios (HRs), with HF patients used as reference, were: stroke 1.35[1.30–1.40]; COPD 1.29[1.25–1.34]; and cancer 1.19[1.14–1.23]. The five-year incidence of nursing home admission was 6.6% for stroke, and substantially lower in patients with HF(2.6%), COPD(2.6%) and cancer (1.5%). The adjusted HRs were (HF reference): stroke, 2.44 [2.23–2.68]; COPD 1.01 [0.91–1.13] and cancer 0.76 [0.67–0.86]. Living alone, older age, diabetes, chronic kidney disease, depression and dementia predicted a higher likelihood of both types of care. Conclusions In patients with HF, stroke, COPD or cancer 5-year risk of domiciliary care and nursing home admission, ranged from 19–25% and 1–7%, respectively. Patients with stroke had the highest rate of domiciliary care and were more than twice as likely to be admitted to a nursing home, compared to patients with the other conditions.

AIM Randomized clinical trials (RCTs) allocating type 2 diabetes patients to treatment with sodium-glucose transport protein 2 (SGLT-2) inhibitors or placebo have found significant effects on the risk of heart failure and modest effects on mortality. In the wake of the first trials, a number of observational studies have been conducted, some of these reporting a mortality reduction of 50% compared to active comparators. In this review, we systematically assess and compare the results on all-cause mortality, cardiovascular mortality and heart failure hospitalization observed in RCTs with the results obtained in observational studies. METHOD We performed a systematic bibliographical search including cardiovascular outcome trials and observational studies assessing the effect of SGLT-2 inhibitors on mortality and heart failure. RESULTS Seven RCTs and 23 observational studies were included in the current review. The observed heterogeneity between study results for all-cause mortality (p-interaction

Objectives This study aims to identify patients with nonischemic heart failure who are more likely to benefit from implantable cardioverter-defibrillator (ICD) implantation by use of established risk prediction models. Background It has been debated whether an ICD for primary prevention reduces mortality in patients with nonischemic heart failure. Methods The Seattle Heart Failure Model (SHFM) predicts all-cause mortality whereas the Seattle Proportional Risk Model (SPRM) predicts the proportion of sudden cardiac death (SCD) versus nonsudden death, with a higher score indicating a greater proportion of SCD. We report the effect of ICD implantation on all-cause mortality and SCD, according to median SPRM and SHFM scores in all 1,116 patients enrolled in the DANISH (Danish study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on mortality) trial. Results Among patients with an SPRM score above the median (n = 558), ICD implantation reduced all-cause mortality (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43 to 0.94), whereas patients with lower SPRM scores (n = 558) had no effect (HR: 1.08; 95% CI: 0.78 to 1.49, p for interaction = 0.04). The corresponding numbers for SHFM score above and below the median were HR: 0.84; 95% CI: 0.62 to 1.13 and HR: 0.82; 95% CI: 0.53 to 1.28, respectively (p for interaction = 0.980). In 177 patients with upper SPRM/upper SHFM, ICD implantation reduced all-cause mortality (HR: 0.45; 95% CI: 0.25 to 0.80) when compared to 381 patients with lower SPRM/upper SHFM (HR: 1.09; 95% CI: 0.76 to 1.55) (p for interaction Conclusions Nonischemic heart failure patients with high predicted relative likelihood of SCD, as estimated by higher SPRM score, seemed to benefit from ICD implantation. (DANISH [Danish ICD Study in Patients With Ditaled Cardiomyopathy]; NCT00542945)

Objectives: This study aimed to evaluate the incidence and causes of hospitalization in the year preceding death of patients with heart failure (HF). Background: Hospitalizations in HF are common, especially in the last period of the lives of patients with HF, but little is known about hospitalization burden and causes during this phase of the disease. Methods: From Danish nationwide registries, we identified patients who died in the period 2001–2016 after having experienced HF for at least 1 year, and examined hospitalizations during the last year of life in age- and sex-stratified analyses. Results: We included 32,157 patients. Median age at time of death was 81 years; 39% were women. A total of 26,561 (84%) patients were hospitalized at least once during the last year of life. The patients experienced a median of 2 (1 to 3) hospitalizations and spent 14 (3 to 31) days in the hospital. Of all hospitalizations (n = 80,362), 9,644 (12%) were due to HF, 14,738 (18%) due to other cardiovascular (CV) causes, and 51,696 (64%) due to non-CV causes (p < 0.001). The frequency of hospitalizations increased toward death, but the domination of non-CV causes remained consistent throughout the year, regardless of age and sex. If we included diagnoses covering renal insufficiency in the definition of HF hospitalizations, non-CV hospitalizations remained dominant (58%). Conclusions: During the last year alive, patients with HF were more often hospitalized due to non-CV causes rather than HF. These findings warrant more focus on a multidisciplinary approach toward end-of-life care in patients with HF.

Background The aim of the study was to investigate the associated risk of stroke after discharge of infective endocarditis (IE) in patients with stroke during IE admission compared with patients without stroke during IE admission. Methods Using Danish nationwide registries, we identified nonsurgically treated patients with IE discharged alive in the period from 1996 to 2016. The study population was grouped into (1) patients with stroke during IE admission and (2) patients without stroke during IE admission. Multivariable adjusted Cox proportional-hazard analysis was used to compare the associated risk of stroke between groups. Results We identified 4,284 patients with IE, of whom 239 (5.6%) had a stroke during IE admission. We identified differentials in the associated risk of stroke during follow-up between groups (P = .006 for interaction with time). The associated risk of stroke was higher in patients with stroke during IE admission with a 1-year follow-up, HR = 3.21 (95% CI 1.66-6.20), compared with patients without stroke during IE admission. From 1 to 5 years of follow-up, we identified no difference in the associated risk of stroke between groups, HR = 0.91 (95% CI 0.33-2.50). Conclusions Patients with nonsurgically treated IE with a stroke during IE admission were at significant higher associated risk of subsequent stroke within the first year of follow-up as compared with patients without a stroke during IE admission. This risk difference was not evident beyond 1 year of discharge. These findings underline the need for identification of causes and mechanisms of recurrent strokes after IE to develop preventive means.

Aims: We examined the prognostic importance of N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) and troponin T (TnT) in heart failure patients with and without diabetes. Methods and results: We measured NT‐proBNP and TnT in the biomarker substudy of the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM‐HF). Of 1907 patients, 759 (40%) had diabetes. Median TnT in patients with diabetes was 18 (interquartile range 11–27) ng/L and 13 (9–21) ng/L in those without (P

Context Hypothyroidism has detrimental effects on the cardiovascular system, but controversy remains concerning the benefits of levothyroxine (L-T4) substitution in patients with heart failure (HF). Objective Examining the effects of L-T4 in patients with HF. Design Retrospective cohort study. Setting and participants All Danish citizens aged ≥18 years diagnosed with HF between 1997 and 2012. L-T4 treatment was identified from nationwide registers. Incidence rate ratios (IRRs) were calculated with Poisson regression models. Main outcome measures All-cause mortality, myocardial infarction (MI), cardiovascular death, and major adverse cardiovascular events (MACEs). Results A total of 224,670 patients were diagnosed with HF [mean age 70.7 (SD ± 14.7) years, 53% male]. Of these, 6560 patients were treated with L-T4 at baseline, and 9007 patients initiated L-T4 during follow-up. A total of 209,103 patients did not receive L-T4. During a median follow-up of 4.8 years [interquartile range (IQR) 9.2] 147,253 patients died. Increased risk of all-cause mortality (IRR 1.25; 95% CI, 1.21 to 1.29; IRR 1.13; 95% CI, 1.10 to 1.16), cardiovascular death (IRR 1.23; 95% CI, 1.18 to 1.27; IRR 1.11; 95% CI, 1.08 to 1.15), and MACE (IRR 1.26; 95% CI, 1.22 to 1.31; IRR 1.05; 95% CI, 1.02 to 1.09) was observed for treatment ongoing at baseline and initiated during follow-up, respectively. Increased risk of MI (IRR 1.32; 95% CI, 1.23 to 1.41) was observed for ongoing treatment, and reduced risk (IRR 0.87; 95% CI, 0.81 to 0.93) was observed for incident treatment. Conclusion Ongoing and incident L-T4 treatment in patients with HF was associated with an increased risk of all-cause mortality, cardiovascular death, and MACE. Increased risk of MI was observed for ongoing treatment, and reduced risk was observed for incident treatment.

Background Ergot-derived dopamine agonists are thought to induce fibrotic changes in cardiac valve leaflets. We sought to determine the incidence of heart valve disease in women treated with bromocriptine compared with age and sex matched controls from the background population. Methods In nationwide Danish registries we identified female patients treated with bromocriptine in the period 1995–2018. Patients were included at date of second redeemed prescription and were matched 1:5 with controls from the background population based on age, sex and year of inclusion by use of incidence density sampling. The outcomes were hospital admission for or outpatient diagnosis of heart valve disease, and death as competing risk. Incidence rates, cumulative incidence curves, and adjusted cox-proportional hazard models adjusted for cardiovascular risk factors were used to assess outcomes in bromocriptine users versus controls. Results A total of 3035 female bromocriptine users and 15,175 matched controls were included. Median age at inclusion was 32 years (Q1–Q3, 28–37 years). Both bromocriptine users and controls had few comorbidities and low use of concomitant pharmacotherapy. Within 10 years of follow-up, 11 patients (0.34%, 95% CI 0.13–0.55%) and 44 controls (0.29%, 95% CI 0.20–0.37) met the primary endpoint of heart valve disease, p = 0.63. The adjusted cox regression analysis yielded a hazard ratio of 0.96 (95% confidence interval (CI) 0.55–1.69, p = 0.89). Conclusions Treatment initiation with ergot-derived dopamine agonist bromocriptine in younger women with few comorbidities, was associated with a low absolute long-term risk of heart valve disease, not significantly different from the risk in age and sex matched population controls. Thus, indicating a low clinical yield of pre-treatment echocardiographic screening in this patient population in accordance with current guidelines.

Objectives: There is a paucity of data on the risk of nursing home admission or domiciliary care initiation according to time to intravenous thrombolysis for ischemic stroke. We investigated the association between time to intravenous thrombolysis and the composite of nursing home admission or domiciliary care initiation in patients with acute ischemic stroke. Materials and Methods: In this nationwide cohort study, all stroke patients treated with intravenous thrombolysis (2011–2015) and alive at discharge were identified from the Danish Stroke Registry and other nationwide registries. The composite of nursing home admission or domiciliary care initiation one year post-discharge according to time to thrombolysis was examined with multivariable Cox regression. Results: The study population comprised 4,349 patients (median age 67 years [25th-75th percentile 57–75], 65.2% men). The median National Institutes of Health Stroke Scale score at presentation was 5, and the median time from symptom-onset to initiation of thrombolysis was 143 min. The absolute 1-year risk of the composite endpoint was 14.0% (95%CI, 11.5–16.8%) in the ≤90 min group, 16.6% (15.1–18.1%) in the 91–180min group, and 16.0% (14.0–18.2%) in the 181–270 min group. Compared with thrombolysis ≤90 min, time to thrombolysis between 91–180 min and 181–270 min was associated with a significantly higher risk of the composite endpoint (hazard ratio 1.31 [1.04–1.65] and 1.47 [1.14–1.91], respectively). Conclusions: In patients admitted with ischemic stroke, increasing time to thrombolysis was associated with a greater risk of the composite of nursing home admission or domiciliary care initiation. Continued efforts to shorten the time delay from symptom-onset to initiation of thrombolysis are warranted.

Aims Patients undergoing aortic valve replacement (AVR) for severe aortic stenosis have a 6–16% prevalence of occult cardiac amyloidosis. Carpal tunnel syndrome (CTS) is common in cardiac amyloidosis, but whether prior CTS surgery has a prognostic impact in patients undergoing AVR is unknown. This study examined the association between prior CTS surgery and adverse cardiovascular outcomes in patients treated with AVR. Methods and results Using Danish nationwide registries, we retrospectively identified patients undergoing first-time AVR from 2005 to 2018, examining the association between previous CTS and adverse cardiovascular outcomes the following 5 years after the AVR procedure. Cumulative incidence functions and adjusted Cox proportional hazard models were used to assess differences. Among 19,211 patients undergoing AVR, 2.5% (n = 472) had prior CTS surgery. Patients in the CTS-cohort were significantly older (median age 75.7 [IQR 68.1–82.3] vs 73.7 [IQR 66.0–79.6]), more often female and had more comorbidities. Prior CTS surgery was not associated with differences in hospitalization for heart failure (11.2% [95% CI 8.3–14.7] vs 9.4% [95% CI 9.0–9.9]), atrial fibrillation (11.1% [95% CI 8.2–14.5] vs 11.2% [95% CI 10.8–11.7]) or pacemaker implantation (6.2% [95% CI 4.0–9.0] vs 5.1% [95% CI 4.8–5.5]). The 5-year mortality (32.8% [27.6–38.0] vs 25.2% [24.5–25.9]) was higher in the CTS-cohort. CTS was significantly associated with increased 5-year mortality (HR 1.27 [1.05–1.53]) in crude models, however, after multivariable adjustment prior CTS surgery was not associated with adverse cardiovascular outcomes. Conclusion Previous CTS surgery was not associated with increased risk for adverse cardiovascular outcomes after AVR.

Background: \ud GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes.\ud \ud Methods: \ud We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age, and eGFR. We searched PubMed for eligible trials reporting MACE (ie, cardiovascular death, myocardial infarction, or stroke), up to June 9, 2021. We meta-analysed data from published randomised placebo-controlled trials testing either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes. We restricted the search to trials of more than 500 patients with a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This meta-analysis was registered on PROSPERO, CRD42021259711.\ud \ud Findings: \ud Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80–0·93]; p

Objective. The aim of this study was to examine the long-term risk of heart failure (HF) and all-cause mortality, in patients discharged alive following hospitalization for myocarditis. Background. Prognosis in patients with apparently uncomplicated myocarditis is in general perceived as good, but data on long-term outcomes are sparse. Methods. From nationwide Danish registries we included patients without prior cardiac disease, discharged alive with a first-time diagnosis of myocarditis 1996���2016. Patients were matched 1:10 by age- and sex, with controls from the general population. Risk of HF hospitalization and death in cases and controls was compared by use of adjusted Cox regression analyses. Results. We identified 1557 patients with a first-time diagnosis of myocarditis, 72% men, median age 39 years. Patients with myocarditis had more hypertension, diabetes, and cancer, and received more pharmacotherapy prior to hospitalization compared to matched controls. During a mean follow-up of 8.5 years, the event rate of HF hospitalization was 8.7 vs. 2.2 per 1000 patient-years (py) in cases and controls; HR 4.59 (95% CI; 3.58���5.88) and for all-cause mortality, event rate 21.9 vs 11.2 per 1000 py; HR 2.10 (95% CI; 1.82���2.43). Among 784 patients with no events or HF medication one year after diagnosis, risk of HF hospitalization (HR 2.15; 95% CI; 1.18���3.92), and all-cause mortality (HR 1.62; 95% CI; 1.21���2.16) remained elevated compared to matched controls. Conclusion. Myocarditis in younger patients without prior cardiac disease was associated with a long-term excess risk of HF hospitalization, and death, even in patients free of events and HF medication 1 year after discharge.HighlightsMyocarditis ranges from chest discomfort to severe heart failure.In most patients, left ventricular ejection fraction recovers but the long-term adverse cardiac risk is unknown.Patients with myocarditis and no prior cardiac disease were at higher risk of death and heart failureRoutine follow-up may be warranted following an episode of acute myocarditis. Myocarditis ranges from chest discomfort to severe heart failure. In most patients, left ventricular ejection fraction recovers but the long-term adverse cardiac risk is unknown. Patients with myocarditis and no prior cardiac disease were at higher risk of death and heart failure Routine follow-up may be warranted following an episode of acute myocarditis.

Background Hyperkalaemia often limits the use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure and reduced ejection fraction (HFrEF), denying these patients a life-saving therapy. Purpose To determine whether treatment with the sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin reduces the risk of hyperkalaemia associated with MRA use in patients with HFrEF. Methods The risk of developing mild hyperkalaemia (potassium >5.5 mmol/L) and moderate/severe hyperkalaemia (>6.0 mmol/L) was examined in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) according to background MRA use, and randomized treatment assignment, by use of Cox regression analyses. Results Overall, 3370 (70.1%) patients in DAPA-HF were treated with an MRA. Mild hyperkalaemia and moderate/severe hyperkalaemia occurred in 182 (11.1%) and 23 (1.4%) patients treated with dapagliflozin as compared to 204 (12.6%) and 40 (2.4%) of patients given placebo (Table and Figure). This yielded a hazard ratio (HR) of 0.86 (0.70–1.05) for mild hyperkalaemia and 0.50 (0.29, 0.85) for moderate/severe hyperkalaemia, comparing dapagliflozin to placebo. Conclusions Patients with HFrEF and taking a MRA who were randomized to dapagliflozin had half the incidence of moderate/severe hyperkalaemia, compared with those randomized to placebo. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): DAPA-HF study was funded by AstraZeneca

Background Heart failure (HF) is a progressive disease characterized by risk of congestion and often accompanied by a significant burden of comorbidities. At the time of HF diagnosis, these are associated with a poor outcome, but it is relatively unknown whether hospitalization due to new-onset comorbidities carries the same subsequent mortality risk as hospitalization for worsening HF. Purpose To assess one-year mortality risk after hospitalization due to new-onset chronic comorbidity compared to a hospitalization with worsening HF in a nationwide cohort of patients with HF. Methods In Danish administrative registers, we identified all patients, aged 40–95 years with a first-time HF diagnosis from 2000 through 2016. Patients were included if they survived the initial 120 days and collected prescribed renin-angiotensin system inhibitor and beta-blocker. In analyses stratified on age and baseline burden of comorbidity (based on Charlson Comorbidity Index (CCI) excluding myocardial infarction and HF, we estimated absolute one-year mortality risk continuously during follow-up, using landmarking and flexible semi-parametric methods. If a patient had a comorbidity hospitalization equivalent to an increase in his/ her CCI or a HF hospitalization, one-year mortality risk was estimated immediately hereafter. In analyses assuming constant risks during follow-up, we calculated absolute risks and risk ratios for new comorbidity- or HF hospitalizations compared to patients without events. Results We included 81,788 patients, median age 72 (Q1-Q3:63–80), 36% women. At baseline, 57% had CCI=0, 22% CCI=1, 9% CCI=2 and 12% CCI≥3. High age and baseline CCI were associated with increased mortality risk throughout follow-up. Both new comorbidity- and HF hospitalizations at any time during follow-up were associated with increased mortality risk (p Conclusions For patients with HF, hospitalization for new-onset chronic comorbidity was associated with at least the same mortality risk as worsening HF, independently of age. This finding highlights the prognostic impact of comorbidity for patients with HF and warrants further investigations in the mechanisms underlying the mortality. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Danish Heart Foundation

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT).METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years.RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark.CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

BACKGROUND: It is estimated that 5% of patients with sarcoidosis have clinically manifest cardiac involvement, although autopsy and imaging studies suggest a significantly higher prevalence of cardiac involvement. There is a paucity of contemporary data on the risk of adverse cardiac outcomes, particularly heart failure (HF), in patients with sarcoidosis.OBJECTIVES: The purpose of this study was to examine the long-term risk of HF and other adverse cardiac outcomes in patients with sarcoidosis compared with matched control subjects.METHODS: In this cohort study, all patients age ≥18 years with newly diagnosed sarcoidosis (1996 to 2016) were identified through Danish nationwide registries and matched 1:4 by age, sex, and comorbidities with control subjects from the background population without sarcoidosis.RESULTS: Of the 12,042 patients diagnosed with sarcoidosis, 11,834 patients were matched with 47,336 subjects from the background population (median age: 42.8 years [25th to 75th percentile: 33.1 to 55.8 years], 54.3% men). The median follow-up was 8.2 years. Absolute 10-year risks of outcomes were as follows: HF: 3.18% (95% confidence interval [CI]: 2.83% to 3.57%) for sarcoidosis patients and 1.72% (95% CI: 1.58% to 1.86%) for the background population; the composite of ICD implantation, ventricular arrhythmias, and cardiac arrest: 0.96% (95% CI: 0.77% to 1.18%) for sarcoidosis patients and 0.45% (95% CI: 0.38% to 0.53%) for the background population; the composite of pacemaker implantation, atrioventricular block, and sinoatrial dysfunction: 0.94% (95% CI: 0.75% to 1.16%) for sarcoidosis patients and 0.51% (95% CI: 0.44% to 0.59%) for the background population; atrial fibrillation or flutter: 3.44% (95% CI: 3.06% to 3.84%) for sarcoidosis patients and 2.66% (95% CI: 2.49% to 2.84%) for the background population; and all-cause mortality: 10.88% (95% CI: 10.23% to 11.55%) for sarcoidosis patients and 7.43% (95% CI: 7.15% to 7.72%) for the background population.CONCLUSIONS: Patients with sarcoidosis had a higher associated risk of HF and other adverse cardiac outcomes compared with matched control subjects.

Background Mortality is increased following a hospitalization for decompensated heart failure ( HF ), during which diuretics are usually intensified. It is unclear how risk is affected after outpatient intensification of diuretic therapy for HF . Methods and Results From nationwide administrative registers, we identified all Danish patients who were diagnosed with HF from 2001 to 2016 and received angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker and β blocker within 120 days. Subsequent follow‐up tracked progressive events of diuretic intensification and HF hospitalization. Intensification events were defined as new addition or doubling of loop diuretic or addition of thiazide to loop diuretic. These events were included in multivariable Cox regression models, calculating 1‐year mortality hazard after each year since inclusion. Patients with an intensification event or hospitalization were risk set matched to 2 nonworsened HF controls and absolute 1‐year mortality risks were calculated using Kaplan‐Meier estimates. We included 74 990 patients, their median age was 71 years, and 36% were women. Intensification events were associated with significantly increased mortality at all times during follow‐up. One‐year mortality was 18.0% after an intensification event, 22.6% after HF hospitalization, and 10.4% for matched controls with neither. In a multivariable Cox model adjusted for age, sex, ischemic heart disease, atrial fibrillation, chronic obstructive pulmonary disease, and diabetes mellitus, the hazard ratio for 1‐year death after an intensification event was 1.75 (95% CI , 1.66–1.85), and it was 2.28 (95% CI , 2.16–2.41) after HF hospitalization. Conclusions In a nationwide cohort of patients with HF , outpatient intensification events were associated with almost 2‐fold risk of mortality during the next year. Although HF hospitalization was associated with a higher risk, the need to intensify diuretics in the outpatient setting is a signal to review and intensify efforts to improve HF outcomes.

Background In randomised clinical trials, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium–glucose cotransporter 2 (SGLT-2) inhibitors reduced cardiovascular events in patients with type 2 diabetes (T2D) at high cardiovascular risk, as compared to standard care. However, data comparing these agents in patients with T2D who are at moderate risk is sparse. Methods From Danish national registries, we included patients with T2D previously on metformin monotherapy, who started an additional glucose-lowering agent [GLP-1 RA, SGLT-2 inhibitor, dipeptidyl peptidase-4 (DPP-4) inhibitor, sulfonylurea (SU), or insulin] in the period 2010-2016. Patients with a history of cardiovascular events [heart failure (HF), myocardial infarction (MI) or stroke] were excluded. Patients were followed for up to 2 years. Cause-specific adjusted Cox regression models were used to compare the risk of hospitalisation for HF, a composite endpoint of major adverse cardiovascular events (MACE) (MI, stroke or cardiovascular death), and all-cause mortality for each add-on therapy. Patients who initiated DPP-4 inhibitors were used as reference. Results The study included 46,986 T2D patients with a median age of 61 years and of which 59% were male. The median duration of metformin monotherapy prior to study inclusion was 5.3 years. Add-on therapy was distributed as follows: 13,148 (28%) GLP-1 RAs, 2343 (5%) SGLT-2 inhibitors, 15,426 (33%) DPP-4 inhibitors, 8917 (19%) SUs, and 7152 (15%) insulin. During follow-up, 623 (1.3%, range 0.8-2.1%) patients were hospitalised for HF—hazard ratios (HR) were 1.11 (95% CI 0.89–1.39) for GLP-1 RA, 0.84 (0.52–1.36) for SGLT-2 inhibitors, 0.98 (0.77–1.26) for SU and 1.54 (1.25–1.91) for insulin. The composite MACE endpoint occurred in 1196 (2.5%, range 1.5–3.6%) patients, yielding HRs of 0.82 (0.69–0.97) for GLP-1 RAs, 0.79 (0.56–1.12) for SGLT-2 inhibitors, 1.22 (1.03–1.49) for SU and 1.23 (1.07–1.47) for insulin. 1865 (3.9%, range 1.9–9.0%) died from any cause during follow-up. HRs for all-cause mortality were 0.91 (0.78–1.05) for GLP-1 RAs, 0.79 (0.58–1.07) for SGLT-2 inhibitors, 1.13 (0.99–1.31) for SU and 2.33 (2.08–2.61) for insulin. Conclusion In a nationwide cohort of metformin-treated T2D patients and no history of cardiovascular events, the addition of either GLP-1 RA or SGLT-2 inhibitor to metformin treatment was associated with a similar risk of hospitalisation for HF and death, and a lower risk of MACE for GLP-1 RA when compared with add-on DPP-4 inhibitors. By contrast, initiation of treatment with SU and insulin were associated with a higher risk of MACE. Additionally, insulin was associated with an increased risk of all-cause mortality and hospitalisation for HF.

Background: Heart failure (HF) in patients with type 2 diabetes mellitus (T2D) has received growing attention. We examined the effect of HF development on prognosis compared with other cardiovascular or renal diagnoses in patients with T2D. Methods and Results: Patients with new T2D diagnosis patients were identified between 1998 and 2015 through Danish nationwide registers. At yearly landmark timepoints after T2D diagnosis, we estimated the 5-year risks of death, 5-year risk ratios, and decrease in lifespan within 5 years associated with the development of HF, ischemic heart disease, stroke, peripheral artery disease, and chronic kidney disease. A total of 153 403 patients with newly diagnosed T2D were followed for a median of 9.7 years (interquartile range, 5.8–13.9) during which 48 087 patients died. The 5-year risk ratio of death associated with HF development 5 years after T2D diagnosis was 3 times higher (CI, 2.9–3.1) than patients free of diagnoses (CI, 2.9–3.1). Five-year risk ratios were lower for ischemic heart disease (1.3 [1.3–1.4]), stroke (2.2 [2.1–2.2]), chronic kidney disease (1.7 [1.7–1.8]), and peripheral artery disease (2.3 [2.3–2.4]). The corresponding decrease in lifespan within 5 years when compared with patients free of diagnoses (in months) was HF 11.7 (11.6–11.8), ischemic heart disease 1.6 (1.5–1.7), stroke 6.4 (6.3–6.5), chronic kidney disease 4.4 (4.3–4.6), and peripheral artery disease 6.9 (6.8–7.0). HF in combination with any other diagnosis imposed the greatest risk of death and decrease in life span compared with other combinations. Supplemental analysis led to similar results when stratified according to age, sex, and comorbidity status, and inclusion period. Conclusions: HF development, at any year since T2D diagnosis, was associated with the highest 5-year absolute and relative risk of death, and decrease in lifespan within 5 years, when compared with development of other cardiovascular or renal diagnoses.

BACKGROUND: Heart failure (HF) is widely associated with a median survival of 5 years. However, population level data on survival and HF progression has been limited for key subgroups. We assessed survival and HF progression, defined as hospitalization or outpatient diuretic intensification in patients ≤70 years without severe comorbidity, who received relevant medical therapy.METHODS: From administrative registers, we identified all Danish patients ≤70 years diagnosed with HF 2000-2012 without severe comorbidity, survived for 120 days to receive angiotensin converting enzyme inhibitors (ACE-I)/angiotensin receptor blocker (ARB) and beta blocker. Risk of death or progression of HF was assessed with Kaplan-Meier and Aalen Johansen estimators, respectively. Cox regression models were used to identify factors associated with risk of death.RESULTS: We included 19,985 patients, median age 61, 25% women - 1/3 of all HF patients ≤70 years. We excluded 237 patients who died within 120 days and 21,065 due to severe comorbidity. Five-year cumulative incidence of all-cause death was 14% (95%-confidence interval [CI]:13-14). Risk of death was increased for patients first diagnosed in hospital compared to outpatient clinics (hazard ratio: 1.51, 95%-CI:1.38-1.65, p < 0.001). Five-year cumulative incidence of HF hospitalization: 18% (95%-CI, 18-19) and intensification of diuretic therapy: 14% (95%-CI, 14-15).CONCLUSIONS: In patients ≤70 years without severe comorbidity, five-year mortality was only 14% and almost 2/3 were alive after 5 years without evident HF progression. Discussion of prognosis should be tailored to age and health status to provide realistic expectations for patients newly diagnosed and treated with recommended therapies for HF.

Background: Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). Methods: Eligibility criteria in PARADIGM-HF included New York Heart Association functional class II to IV, left ventricular ejection fraction ≤40%, and elevated natriuretic peptides: BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL (for patients with HF hospitalization within 12 months, BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL). BNP and NT-proBNP were measured simultaneously at screening and only patients who fulfilled entry criteria for both natriuretic peptides were included in the present analysis. The BNP/NT-proBNP criteria were not different for patients in atrial fibrillation. Estimated glomerular filtration rate 2 was a key exclusion criterion. Results: The median baseline concentration of NT-proBNP was 2067 (Q1, Q3: 1217–4003) and BNP 318 (Q1, Q3: 207–559), and the ratio, calculated from the raw data, was ≈6.25:1. This ratio varied considerably according to rhythm (atrial fibrillation 8.03:1; no atrial fibrillation 5.75:1) and with age, renal function, and body mass index but not with left ventricular ejection fraction. Each peptide was similarly predictive of death (all-cause, cardiovascular, sudden and pump failure) and heart failure hospitalization, for example, cardiovascular death: BNP hazard ratio, 1.41 (95% CI, 1.33–1.49) per 1 SD increase, P P Conclusions: The ratio of NT-proBNP to BNP in heart failure and reduced ejection fraction appears to be greater than generally appreciated, differs between patients with and without atrial fibrillation, and increases substantially with increasing age and decreasing renal function. These findings are important for comparison of natriuretic peptide concentrations in heart failure and reduced ejection fraction.

Aims: The importance of intra-ventricular conduction delay (IVCD), the incidence of new IVCD and its relationship to outcomes in heart failure and reduced ejection fraction (HFrEF) are not well studied. We addressed these questions in the PARADIGM-HF and ATMOSPHERE trials. Methods and results: The risk of the primary composite outcome of cardiovascular death or heart failure hospitalization and all-cause mortality were estimated by use of Cox regression according to baseline QRS duration and morphology in 11 861 patients without an intracardiac device. At baseline, 1789 (15.1%) patients had left bundle branch block (LBBB), 524 (4.4%) right bundle branch block (RBBB), 454 (3.8%) non-specific IVCD, 2588 (21.8%) ‘mildly abnormal’ QRS (110–129 ms) and 6506 (54.9%) QRS

Aim: To examine the rates of all‐cause mortality and heart failure (HF) readmission in patients hospitalized with decompensated HF according to HF duration – new‐onset HF and worsening of chronic HF. Methods and results: In this nationwide observational cohort study, 17 176 patients were included at first hospital admission for HF in the period 2013–2015 using data from Danish nationwide registries. In total, 8860 (51.6%) patients were admitted with new‐onset HF and 8316 (48.4%) with worsening of chronic HF. Patients with worsening of chronic HF were characterized by a greater comorbidity burden compared with patients with new‐onset HF. The rates of outcomes were examined by multivariable Cox regression models, adjusted for age, sex, and comorbidity. Worsening of chronic HF was associated with a higher rate of the composite endpoint of all‐cause mortality or HF readmission [hazard ratio (HR) 1.37, 95% confidence interval (CI) 1.31–1.43], all‐cause mortality (HR 1.22, 95% CI 1.16–1.28), and HF readmission (HR 1.81, 95% CI 1.69–1.93) compared with new‐onset HF. There was an interaction between atrial fibrillation (AF), HF duration, and outcome: in worsening of chronic HF, the rate of the composite endpoint was higher in patients with AF compared with those without (HR 1.12, 95% CI 1.07–1.19), whereas in new‐onset HF, the rate of the composite endpoint was lower in patients with AF compared with those without (HR 0.91, 95% CI 0.85–0.96) (P‐value for interaction

Aims: The role of microvascular complications in the risk conferred by diabetes in heart failure with reduced ejection fraction (HFrEF) is unknown. Methods and results: We studied 2707 HFrEF patients in the Beta‐blocker Evaluation of Survival Trial (BEST), stratified into three groups: no diabetes and diabetes without or with microvascular complications (neuropathy, nephropathy, or retinopathy). The risks of the composite of cardiovascular death or heart failure hospitalization, and all‐cause death, were studied using Cox regression analyses adjusted for other prognostic variables. Overall, 964 (36%) patients had diabetes, of which 313 (32%) had microvascular complications. Patients with microvascular complications had more severe symptoms (New York Heart Association class IV 12% vs. 9% diabetes with no complications and 7% no diabetes), and worse quality of life (Minnesota Living with Heart Failure median score 60 vs. 54 and 51 points). In patients with diabetes and complications, the rate of the composite outcome was 50 per 100 person‐years of follow‐up (compared with 34 and 29 in those with diabetes and no microvascular complications and participants without diabetes, respectively). Compared to patients without diabetes, the adjusted hazard ratio (HR) for the composite outcome was 1.44 [95% confidence interval (CI) 1.22–1.70] and 1.18 (95% CI 1.03–1.35) for patients with diabetes with and without complications, respectively. The risk of all‐cause mortality was similarly elevated: adjusted HR 1.42 (95% CI 1.16–1.74) and 1.20 (95% CI 1.01–1.42), respectively. Conclusion: In HFrEF, diabetes with microvascular complications is associated with worse symptoms and outcomes than diabetes without microvascular complications. Prevention of microvascular complications has the potential to improve HFrEF outcomes.

AIMS: The landmark STICH trial found that surgical revascularization compared to medical therapy alone improved survival in patients with heart failure (HF) of ischemic etiology and an ejection fraction (EF) ≤35%. However, the interaction between the burden of medical comorbidities and the benefit from surgical revascularization has not been previously described in patients with ischemic cardiomyopathy. METHODS: The STICH trial (ClinicalTrials.gov Number: NCT00023595) enrolled patients ≥18 years of age with coronary artery disease amenable to coronary artery bypass grafting (CABG) and an EF ≤35%. Eligible participants were randomly assigned 1:1 to receive medical therapy (MED) (602 patients) or MED/CABG (610 patient). A modified Charlson Comorbidity Index (CCI) based on the availability of data and study definitions was calculated by summing the weighted points for all comorbid conditions. Patients were divided into mild/moderate (CCI 1–4) and severe (CCI ≥5) comorbidity. Cox proportional hazards models were used to evaluate the association between CCI and outcomes. The interaction between severity of comorbidity and treatment effect was assessed with the log-rank test. RESULTS: The study population included 349 patients (29%) with a mild/moderate CCI score and 863 patients (71%) with a severe CCI score. Patients with a severe CCI score had greater functional limitations based on 6-minute walk test and impairments in health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire. A total of 161 patients (Kaplan-Meier [KM] rate = 50%) with a mild/moderate CCI score and 579 patients (KM rate = 69%) with a severe CCI score died over a median follow-up of 9.8 years. After adjusting for baseline confounders, patients with a severe CCI score were at higher risk for all-cause mortality (Hazard Ratio [HR] 1.44, 95% confidence interval [CI] 1.19–1.74; p-value

Aims: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF. Methods and results: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1–Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (

Aims: Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self‐perceived and objective health status. In this study, we examined the association between employment status and the risk of all‐cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF. Methods and results: We identified all patients of working age (18–60 years) with a first HF hospitalization in the period 1997–2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25 571 patients with a first hospitalization for HF, 15 428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%) (all P < 0.0001). Not being part of the workforce was associated with a significantly higher risk of death [hazard ratio (HR) 1.59; 95% confidence interval (CI) 1.50–1.68] and rehospitalization for HF (HR 1.09; 95% CI 1.05–1.14), in analyses adjusted for age, sex, co‐morbidities, education level, calendar time, and duration of first HF hospitalization. Conclusion: Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization.

Aims Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes. Methods and results ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow-up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67–1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71–1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups. Conclusion In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin-converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

Purpose:\ud \ud The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF).\ud \ud Methods:\ud \ud We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models.\ud \ud Results:\ud \ud HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c < 6.0), 20 and 22% had prediabetes (HbA1c 6.0–6.4), respectively. Finally among patients with HFpEF 22% had undiagnosed diabetes (HbA1c > 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups < 0.001. Dysglycemia was also associated with worse outcomes in HFrEF.\ud \ud Conclusions:\ud \ud These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF.